Crystal Engineering of Co-Crystals and Their Relevance to Pharmaceutical Forms Tanise R

University of South Florida Scholar Commons

Graduate Theses and Dissertations Graduate School

2007 Crystal engineering of co-crystals and their relevance to pharmaceutical forms Tanise R. Shattock University of South Florida

Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the American Studies Commons

Scholar Commons Citation Shattock, Tanise R., "Crystal engineering of co-crystals and their relevance to pharmaceutical forms" (2007). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/2361

This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Crystal Engineering of Co-Crystals and their Relevance to Pharmaceutical Forms

Tanise R. Shattock

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemistry College of Arts and Sciences University of South Florida

Major Professor: Michael J. Zaworotko, Ph.D. Mohamed Eddaoudi, Ph.D. Edward Turos, Ph.D. Matthew L. Peterson, Ph.D.

Date of Approval: July 16, 2007

Keywords: Supramolecular Chemistry, Supramolecular Synthon, Hydrogen Bond, Supramolecular Synthesis, Polymorphism

Dedication

For Joshua

Acknowledgements

The author would like to express sincere gratitude and appreciation to her mentor and supervisor Dr. Michael J. Zaworotko for his support over the years and for all the opportunities he has made available for her professional growth and development.

She would also like to thank Dr. Matthew L. Peterson, Dr. Mohamed Eddaoudi and Dr. Edward Turos, her committee members; Dr. Vishweshwar Peddy, Dr. Joanna

Bis, Jennifer McMahon, Gregory McManus, Miranda Cheney, John J. Perry IV, Jason

Perman and all members of the Zaworotko’s Research Group for all their help and advice.

Words cannot adequately express her heartfelt appreciation to Nicholas and

Joshua for their endless love, support, patience and understanding. Finally, she would like to acknowledge and thank her parents, her closest family and friends for their constant support throughout the years of studies.

Table of Contents

List of Tables ix

List of Figures xi

Abstract xvii

Chapter 1. Introduction 1

1.1. Introduction 1

1.1.1. Supramolecular Chemistry 1

1.1.2. Intermolecular Interactions 2

1.1.3. Crystal Engineering 4

1.1.4. Supramolecular Synthons and the Cambridge Structural Database 5

1.1.5. Co-Crystal 8

1.1.6. Preparation of Co-Crystals 10

1.1.7. Pharmaceutical Co-Crystals 12

1.1.8. Polymorphism 21

1.1.9. Summary 23

1.2 References Cited 24

i Chapter 2. The Reliability of the Carboxylic acid-Aromatic Nitrogen

Supramolecular Heterosynthon 39

2.1. Introduction 39

2.2. Results and Discussion 41

2.2.1. CSD Analysis 42

2.2.2.Features of Carboxylic Acid-Aromatic Nitrogen Interaction 45

2.2.3. Crystal Structure Description 50

2.3. Conclusions 67

2.4. Experimental Section 69

2.4.1. Co-crystallization via grinding 69

2.4.2. Co-crystallization via solvent-drop grinding 69

2.4.3. Co-crystallization via melting 69

2.4.4. Co-crystallization via solution evaporation 69

2.4.5. Crystal structure determination 73

2.5. References Cited 77

Chapter 3. The Reliability of the Alcohol−Aromatic Nitrogen Supramolecular

Heterosynthon 83

3.1. Introduction 83

3.2. Results and Discussion 85

3.2.1. Cambridge Structural Database Analysis 85

3.2.2 Features of Hydroxyl···Aromatic Nitrogen Interaction 87

ii 3.2.3. Crystal Structure Description 90

3.3. Conclusions 100

3.4. Experimental Section 104

3.4.1. Synthesis of Co-Crystals 104

3.4.1. Co-crystallization via grinding 105

3.4.2. Co-crystallization via solvent-drop grinding 105

3.4.3. Co-crystallization via melting 105

3.5. References Cited 108

Chapter 4. Delineating the Hierarchy of Supramolecular Heterosynthons:

Carboxylic acid-Aromatic Nitrogen versus Alcohol-Aromatic Nitrogen 113

4.1. Introduction 113

4.2. Results and Discussion 117

4.2.1.CSD Analysis 117

4.2.2 Features of the O-H⋅⋅⋅Narom interaction 119

4.2.3.Crystal Structure Descriptions 121

4.2.4 Methods of Preparation 145

4.3.Conclusions 147

4.4. Experimental Section 148

4.4.1.Syntheses 148

4.4.2. Single-crystal X-ray diffraction. 152

4.5. References Cited 156

iii Chapter 5. Pharmaceutical Co-crystals of Stavudine 160

5.1. Introduction 160

5.2. Results and Discussion 162

5.2.1. Crystal Structure Description 163

5.3. Conclusions 169

5.4. Experimental Section 170

5.4.1 Synthesis 170

5.4.2. Single-crystal X-ray diffraction 171

5.5. References Cited 176

6. Summary and Future Directions 180

6.1.Summary 180

6.2. Future Directions 184

Appendices 188

Appendix 1. Experimental Data for (benzoic acid)2•

1,2-bis(4-pyridyl)ethane 1 189

Appendix 2. Experimental Data for (benzoic acid)2 •

trans-1,2-bis(4-pyridyl)ethylene 2 192

Appendix 3. Experimental Data for benzoic acid •4,4’-bipyridine, 3 195

Appendix 4. Experimental Data for sorbic acid•

1,2-bis(4-pyridinium)ethane sorbate 4 199

iv Appendix 5. Experimental Data for (naproxen)2 •

trans-1,2-bis(4-pyridyl)ethylene 5 202

Appendix 6. Experimental Data for glutaric acid •1,2-bis(4-pyridyl)ethane, 6 205

Appendix 7. Experimental Data for glutaric acid•

trans-1,2-bis(4-pyridyl)ethylene, 7 208

Appendix 8. Experimental Data for oxalic acid•tetramethylpyrazine, 8 211

Appendix 9. Experimental Data for isophthalic acid •

1,2-bis(4-pyridyl)ethane, 9 214

Appendix 10. Experimental Data for (trimesic acid)2 •

trans-(1,2-bis(4-pyridyl)ethylene)3, 11 217

Appendix 11. Experimental Data for trimesic acid•

1,2-bis(4-pyridyl)ethane, 12 220

Appendix 12. Experimental Data for (1-naphthol)2 •

1,2-bis(4-pyridyl)ethane, 13 225

Appendix 13. Experimental Data for (1-naphthol)2 •

trans-1,2-bis(4-pyridyl)ethylene, 14 227

Appendix 14. Experimental Data for 4,4’-biphenol •

1,2-bis(4-pyridyl)ethane, 15 229

Appendix 15. Experimental Data for 4,4’-biphenol •

trans-1,2-bis(4-pyridyl)ethylene, 16 231

v Appendix 16. Experimental Data for hydroquinone •

trans-1,2-bis(4-pyridyl)ethylene, 17 233

Appendix 17. Experimental Data for hydroquinone•

tetramethylpyrazine, 18 235

Appendix 18. Experimental Data for (resorcinol)2•(TMP)3, 19 237

Appendix 19. Experimental Data for 2,7-dihydroxynaphthalene● (TMP)2, 20 239

Appendix 20. Experimental Data for (3-hydroxybenzoic acid)2 • pyrazine, 21 241

Appendix 21. Experimental Data for 4-hydroxybenzoic acid •1,2-bis

(4-pyridinium)ethane • 4- hydroxybenzoate, 22 244

Appendix 22. Experimental Data for (4-hydroxybenzoic acid)2 •

tetramethylpyrazine, 23 247

Appendix 23. Experimental Data for 4-hydroxybenzoic acid •

4-phenylpyridine, 24 249

Appendix 24. Experimental Data for (4-hydroxybenzoic acid)2 • pyrazine, 25 251

Appendix 25. Experimental Data for 4-hydroxybenzoic acid)2 •

tetramethylpyrazine acetonitrile solvate, 26 254

Appendix 26. Experimental Data for 3-hydroxybenzoic acid •

phenylpyridine)2, 27 256

Appendix 27. Experimental Data for 3-hydroxybenzoic acid •

1,2-bis(4-pyridyl)ethane, 28 259

vi Appendix 28. Experimental Data for 3-hydroxybenzoic acid •

4,4’-bipyridine, 29 262

Appendix 29. Experimental Data for 3-hydroxybenzoic acid •

quinoxaline, 30 265

Appendix 30. Experimental Data for (3-hydroxybenzoic acid)2 •

(tetramethylpyrazine)3, 31 268

Appendix 31. Experimental Data for 6-hydroxy-2-naphthoic acid •

trans-1,2-bis(4-pyridyl)ethylene, 32 270

Appendix 32. Experimental Data for 4-hydroxybenzoic acid • trans-1,2-bis

(4-pyridyl)ethylene, 33 272

Appendix 33. Experimental Data for 3-hydroxybenzoic acid •

trans-1,2-bis(4-pyridyl)ethylene, 34 274

Appendix 34. Experimental Data for 3-hydroxypyridinium benzoate, 35 276

Appendix 35. Experimental Data for 3-hydroxypyridinium isophthalate, 36 279

Appendix 36. X-ray powder diffraction patterns of grinding and solvent

drop grinding of isonicotinic acid •1-naphthol, nicotinic acid •1-naphthol,

(nicotinic acid)2 •4,4’-biphenol, (isonicotinic acid)2 •4,4’-biphenol,

(isonicotinic acid)3 •phloroglucinol, (nicotinic acid)3 •phloroglucinol,

(isonicotinic acid)2 •resorcinol, (nicotinic acid)2 •resorcinol. 282

Appendix 37. Diffractograms of Melt Experiments 286

Appendix 39. Experimental Data for (stavudine)3 •melamine, 37 298 vii Appendix 40. Experimental Data for stavudine •2,4,6-triaminopyrimidine

hydrate, 38 301

Appendix 41. Experimental Data for stavudine•2-aminopyridine, 39 303

Appendix 42. Experimental Data for stavudine•4-hydroxybenzoic acid, 40 307

Appendix 43. Experimental Data for stavudine• salicylic acid, 41 311

About the Author End Page

viii

List of Tables

Table 1.1 Covalent and Non-covalent Interactions* 2

Table 1.2 Percentage Occurrence of hydrogen bonding functional groups in APIs 14

Table 2.1. Percentage occurrence, distance ranges, and average distance for

supramolecular synthons I-VI 43

Table 3.1 Geometric features of supramolecular homosynthon V and

supramolecular heterosynthon VI 86

Table 3.2 pKa values of components used in co-crystals 13-20 88

Table 3.3 Crystallographic data and structure refinement parameters for

co-crystals 13-20 102

Table 3.4 Melting points of co-crystals 13-20 and corresponding starting materials 106

Table 3.5 Geometrical parameters of intermolecular interactions for

co-crystals 13-20 107

Table 4.1 CSD statistics on supramolecular synthons that occur

in structures containing only COOH, Narom, and OH 119

Table 4.2 pKa data for 21-36 121

Table 4.3 Summary of supramolecular synthons present in 21-36 145

Table 4.4 Melting point comparison for 21-36 147

ix Table 4.5 Hydrogen Bond Distances and Parameters for 21-36 154

Table 4.6 Hydrogen Bond Distances and Parameters for 21-36 (cont.) 155

Table 4.7 Crystallographic data and structure refinement parameters

for compounds 21-36 156

Table 4.8 Crystallographic data and structure refinement parameters for

compounds 21-36 (cont) 157

Table 5.1 Geometrical Features of Supramolecular Synthons 163

Table 5.2 Geometric Parameters of Intermolecular Interactions for

(stavudine)3●melamine, 37 173

Table 5.3 Geometric Parameters of Intermolecular Interactions for 38-41 174

Table 5.4 Crystallographic Data and structure refinement parameters

for compounds 37-41 175

List of Figures

Figure 1.1. Watson and Crick hydrogen bonding in DNA 3

Figure 1.2 Examples of supramolecular synthons: a) carboxylic acid

homosynthon and b) carboxylic acid···pyridine heterosynthon 5

Figure 1.3. Crystal structure of quinhydrone 8

Figure 1.4. Hydrogen bonded co-crystal structures in the CSD from 1985-2005 9

Figure 1.5. Co-crystal of sulfadimidine and acetylsalicylic acid, VUGMIT 15

Figure 1.6. Co-crystal of barbital and N,N’-bis(m-tolyl)melamine JICVIA10,

sustained by 3-point recognition supramolecular heterosynthon 15

Figure 1.7. Crystal structure of carbamazepine sustained by amide dimer 16

Figure 1.8. Illustrate the co-crystal of carbamazepine•acetylsalicylic acid sustained

by the two point recognition acid-amide supramolecular heterosynthon 17

Figure 1.9. The crystal structure of carbamazepine●saccharin co-crystal 18

Figure 1.10. Crystal structure of cis-itraconazole●succinic acid co-crystals 20

Figure 1.11. The crystal structure of fluoxetine hydrochloride•succinic acid

co-crystal sustained by charge assisted carboxylic acid⋅⋅⋅Cl- interactions 20

Figure 2.1. Molecular components used in co-crystallization of 1-12 41

xi Figure 2.2. Supramolecular heterosynthons that can be formed between

carboxylic acids and aromatic nitrogen 43

Figure 2.3. Histograms of contacts for: a) supramolecular homosynthon I

b) O···N contacts in supramolecular heterosynthon III 45

Figure 2.4. Histograms that present the distribution of the C–N–C angle in a) neutral

aromatic nitrogens and b) protonated aromatic nitrogen moieties 47

Figure 2.5. Illustrate a) discrete three component adducts of co-crystal 1, b) crystal

packing in 1. 51

Figure 2.6 Illustrate (a) Discrete adduct sustained by supramolecular

heterosynthon III (b) packing between adjacent trimeric units. 52

Figure 2.7 Crystal packing of two component units in 3 53

Figure 2.8 Illustrates a discrete three component adduct in 4 54

Figure 2.9 Illustrates discrete adducts of (naproxen)2 •

trans-1,2-bis(4-pyridyl)ethylene, 5 55

Figure 2.10 Crystal packing in (naproxen)2 •trans-1,2-bis(4-pyridyl)ethylene, 5 55

Figure 2.11 Crystal packing in pure glutaric acid 56

Figure 2.12 Crystal structure of glutaric acid● 1,2-bis(4-pyridyl)ethane 6 57

Figure 2.13 Crystal structure of glutaric acid● trans-1,2-bis(4-pyridyl)ethylene, 7 58

Figure 2.14 Crystal packing of oxalic acid● tetramethylpyrazine, 8 59

Figure 2.15 Crystal structure of isophthalic acid●1,2-bis(4-pyridyl)ethane, 9 60

Figure 2.16 Space filling views of a single (10,3)-a network of 12a 63

Figure 2.17 Schematic illustrations of the interpenetration in 12a 64

Figure 3.1 Molecular structures of components used in co-crystallization of 13-20 85

xii Figure 3.2 Histogram of hydrogen bonds of (a) homosynthon V and

(b) heterosynthon VI retrieved from the CSD 87

Figure 3.3 Histograms representing the distribution of carbon-oxygen bond

lengths in a) neutral aromatic hydroxyl moieties (b) neutral aliphatic

hydroxyl moieties (c) deprotonated aromatic hydroxyl moieties and

(d) deprotonated hydroxyl moieties 89

Figure 3.4 Crystal packing in 1-naphthol 90

Figure 3.5 Three component adducts present in the crystal structure of 13 91

Figure 3.6 Crystal packing in 13 91

Figure 3.7 Three component adduct in the crystal structure of 14 92

Figure 3.8 Crystal packing in 14 92

Figure 3.9 Crystal structure of 4,4’-biphenol 93

Figure 3.10 Crystal structure of 4,4’-biphenol●1,2-bis(4-pyridyl)ethane, 15. 94

Figure 3.11 Crystal Packing in 4,4’-biphenol●trans-1,2-bis(4-pyridyl)ethylene, 16 94

Figure 3.12 Crystal Packing in 16, viewed down the b-axis 95

Figure 3.13 Crystal structure of hydroquinone● trans-1,2-bis(4-pyridyl)ethylene, 17 95

Figure 3.14 Crystal Packing in hydroquinone ● trans-1,2-bis(4-pyridyl)ethylene 17 96

Figure 3.15 Crystal structure of hydroquinone ●TMP, 18 97

Figure 3.16 S-shaped discrete unit in the crystal structure 19 99

Figure 3.17 Discrete three component adduct of,7-dihydroxynaphthalene•

(TMP)2 20 100

Figure 4.1 Molecules used in Co-crystallization Experiments 117

xiii Figure 4.2 Possible supramolecular synthons that can form when

OH, Narom and COOH are present in the same structure 118

Figure 4.3 Crystal packing in (3-hydroxybenzoic acid)2 •pyrazine, 21

showing corrugated sheet 122

Figure 4.4 Interdigitation of independent 2D networks in the crystal structure of 21 123

Figure 4.5 Supramolecular synthon in 22 124

Figure 4.6 Crystal packing of 22, showing corrugated sheet 124

Figure 4.7 Crystal packing of adjacent 2D networks in 22 124

Figure 4.8 a) Eight membered molecular rectangular grid formed by six

4-hydroxy benzoic acid and two TMP molecules. b) 2-dimensional

herringbone network in the crystal structure of (4-hydroxybenzoic acid)2•

TMP co-crystal 23 125

Figure 4.9 Crystal packing of adjacent 2D networks in 23 126

Figure 4.10 Crystal structure of 4-hydroxybenzoic acid•4-phenylpyridine 24 127

Figure 4.11 Crystal packing of 24 showing translationally related carboxylic acid

dimer and face to face π-stacked aromatic rings of adjacent 4-phenylpyridine 127

Figure 4.12 Crystal structure of (4-hydroxybenzoic acid)2 •pyrazine, 25 showing

centrosymmetric acid dimers and alcohol-aromatic nitrogen heterosynthons 128

Figure 4.13 Crystal structure of (4-hydroxybenzoic acid)2 ●TMP

acetonitrile solvate, 26 129

Figure 4.14 Crystal structure of 3-hydroxybenzoic acid•(4-phenylpyridine)2, 27 130

Figure 4.15 Crystal packing in 3-hydroxybenzoic acid•.(4-phenylpyridine)2, 27 130

Figure 4.16 Crystal structure of 3-hydroxybenzoic acid•1,2-bis(4-pyridyl)ethane, 28 131

xiv Figure 4.17 Crystal Packing in 3-hydroxybenzoic acid●4,4’-bipyridine, 29 132

Figure 4.18 Crystal Packing in 3-hydroxybenzoic acid •quinoxaline 30 133

Figure 4.19 Discrete 5-component adduct in the crystal structure of

(3-hydroxybenzoic acid)2 ●(TMP)3, 31 133

Figure 4.20 Crystal structure of 6-hydroxynaphthoic acid • trans-1,2-(bis(4-

pyridyl)ethylene 32 134

Figure 4.21 Crystal packing in 6-hydroxynaphthoic acid•trans-1,2-bis

(4-pyridyl)ethylene, 32 135

Figure 4.22 Crystal packing in 4-hydroxybenzoic acid●trans-

1,2-(4-pyridylethylene, 33 showing translationally related zig-zag chains 136

Figure 4.23 Crystal packing in 3-hydroxybenzoic acid●

trans-1,2 (4-pyridyl)ethylene, 34 137

Figure 4.24 (a) Charge-assisted pyridinium-carboxylate supramolecular

heterosynthon IV in 35 (b) Crystal packing in

3-hydroxypyridinium benzoate, 35 139

Figure 4.25 Crystal packing in 3-hydroxypyridinium isophthalate 36 140

Figure 4.26 Crystal structures of the polymorphic forms of

3-hydroxybenzoic acid: (a) Form I and (b) Form II 142

Figure 4.27 Chain motifs generated in 21-34 rationalized via synthons

occurring in the pure carboxylic acid 143

Figure 5.1 Crystal structure of stavudine (Form I) 161

Figure 5.2 (a) Triangular four component supramolecular adduct in co-crystal 37

(b) Hexagonal packing of 3:1 co-crystal of stavudine and melamine, 37 164

xv Figure 5.3 Crystal Packing of 38 showing right handed helices formed through

supramolecular heterosynthons VI and IX 165

Figure 5.4 Illustrates the supramolecular synthons present in co-crystal 39 166

Figure 5.5 Hydrogen bonded infinite chains of stavudine molecules form

terminal O−H···N hydrogen bonds with pyridyl moiety of

2-aminopyridine in co-crystal 39 166

Figure 5.6 Carboxylic acid-amide supramolecular heterosynthon in stavudine•

4-hydroxybenzoic acid 40 167

Figure 5.7 Crystal packing of stavudine●4-hydroxybenzoic acid, 40 168

Figure 5.8 Supramolecular synthon present in stavudine• salicylic acid, 41 168

xvi

Crystal Engineering of Co-Crystals and their Relevance to Pharmaceutical Forms

Tanise R. Shattock

ABSTRACT

The research presented herein focus upon crystal engineering of co-crystals with an emphasis upon the exploration of co-crystals in the context of delineation of the reliability of hydrogen bonded supramolecular synthons and their hierarchies. The approach involves a combination of systematic Cambridge Structural Database analysis and a series of model co-crystal experiments. In addition, the viability of solid state methodologies toward supramolecular synthesis of co-crystals and the effect on polymorphism is also addressed. The application of the acquired knowledge is towards the crystal engineering of pharmaceutical co-crystals. The rational design and synthesis of pharmaceutical co-crystals accomplished by the selection of appropriate co-crystal formers facilitated by analysis of existing crystals structures in the CSD will be demonstrated. The processing of pharmaceutical co-crystals will also be addressed in terms of slurry conversion, solvent drop grinding and solution crystallization.

xvii

1. Introduction

1.1. Introduction

1.1.1. Supramolecular Chemistry

Supramolecular chemistry defined by Jean Marie Lehn as “chemistry beyond the

molecule” is the organization of entities that results from the association of two or more

chemical species held together by non-covalent interactions.1-7 Early inspiration for the

construction of supramolecular entities was obtained from nature and focused upon the

development of macrocyclic receptors for the selective binding of alkali metal cations.8-23

The selective binding of a substrate by a molecular receptor involves molecular recognition, the so called ‘lock and key’ concept enunciated by Emil Fischer.24

Consequently the principles of self-assembly and molecular recognition are intimately

associated paradigms of supramolecular chemistry.

Supramolecular approach to synthesis offers an attractive alternative to traditional

covalent synthesis, as a consequence the field of supramolecular chemistry has grown

around Lehn’s analogy that “supermolecules are to molecules and the intermolecular

bond what molecules are to atoms and the covalent bond”. 25

1 1.1.2. Intermolecular Interactions

The term non-covalent can be applied to a large range of intermolecular

interactions26 including electrostatic interactions (ion-ion, ion-dipole and dipole-dipole

interactions), coordinative bonding (metal-ligand), hydrogen bonding, halogen bonding,

π-π stacking and Van der Waals forces. The utilization of these interactions for directed

self assembly requires an understanding of their strength, distance and directionality.

Gaining a basic knowledge of these factors is a primary focus of this dissertation. A

comparison of selected interactions is presented in Table 1.1.

Table 1.1 Covalent and Non-covalent Interactions*

Bond Energies Building Interaction Products Features (kJ/mol) blocks

H > TΔS Covalent 200 - 400 Atoms Molecules MW: 1 - 1000 Da

Hydrogen Bond 4 - 120 ΔH ≈ TΔS Dipole-Dipole 5 - 50 Molecules Supermolecules MW: 1 - 100 kDa π-π stacking < 50

Van der Waals < 5

*Compiled from Steed, J. W.; Atwood, J. Supramolecular Chemistry, Wiley J.; Chichester, 2000.

Hydrogen bonding 27-29 is perhaps the most reliable design element in the directed

self-assembly of small organic molecules with hydrogen bond donor and acceptor functionalities. The ultimate example of a hydrogen bonded array is provided by nature in the form of the double helix DNA, which is formed between complementary base pairing of cytosine (C) and guanine (G); and adenine (A) and thymine (T).

H N O H N H N N H O N N H N N N N N H N N H O N N H O

GC base pair AT base pair

Figure 1.1. Watson and Crick hydrogen bonding in DNA

Scientists have therefore been inspired by nature to construct supramolecular

structures and materials utilizing hydrogen bonding. The formation of supramolecular

assemblies directed by hydrogen bonds has long been studied with respect to molecular

association both in solution and the solid state. 30-43 In the solid state the hydrogen bond

has been employed as a design element in the crystal engineering70 of small organic molecules.

Halogen bonding is another paradigm that complements the hydrogen bond.44-45 A striking parallelism exists between the properties of these two interactions. Like hydrogen bonding, the halogen bond is a relatively strong and directional non covalent interaction making it well suited for geometry based design. First reported over 140 years ago,46-47 the interaction is of the type B⋅⋅⋅XY, where B represents a Lewis base, commonly nitrogen, oxygen, sulphur or sellinium with a non bonding electron pair and X, a halogen atom commonly iodine. Hassel in his pioneering work used the equivalent term halogen molecule bridge48 to describe these interactions however more recently halogen bonds of the type X⋅⋅⋅:N have been called X-bonds.49 This interaction has been used to control 3 polymorph interconversion 50 and ultimately the generation of numerous supramolecular

solid-state structures.51-59

In the solid state the application of these interactions are in the generation of

multi-component crystals with desired stoichiometry, architecture and ultimately

properties.

1.1.3. Crystal Engineering

A crystal can be viewed as a ‘supramolecule par excellence’ an assembly of molecules crafted by mutual recognition to an amazing level of precision.60 The sequence

of events that lead to the formation of an organic crystal from solution is governed by thermodynamic and kinetic factors which are intertwined in ways that are still hard to understand. As a consequence crystal structure prediction via computational methods 61 still remains elusive.62-69

Crystal engineering is defined by Desiraju as “the understanding of

intermolecular interactions in the context of crystal packing and in the utilization of such

understanding in the design of new solids with desired physical and chemical

properties.” 70 It deals most typically with entirely new phases, sometimes, but not

necessarily, involving well known molecules. Crystal engineering involves the design of crystals with well defined non-covalent connectivities and networks based upon pre- selected molecular components that possess specific functional groups.71-75 The term

crystal engineering was initially introduced by Pepinski in 1955.76 This contemporary

area of research however has its origins in Schmidt’s study of topochemical reactions of

cinnamic acids.77 Technological advances in hardware, software and X-ray

4 crystallographic techniques and the concomitant availability of a large amount of high

quality structural information triggered significant activity in the-eighties and nineties.

Pioneering works by Etter 78 and Desiraju 79 focused upon using the Cambridge

Structural Database (CSD) 80 to analyze and interpret non-covalent bonding patterns in an

effort to design functional solids. Crystal engineering represents a paradigm for the

synthesis of new crystalline phases with predictable stoichiometry and architecture.

1.1.4. Supramolecular Synthons and the Cambridge Structural Database

Supramolecular synthons79 are structure determining patterns81 or motifs78 that encode the molecular recognition information during the crystallization process.

Supramolecular synthons may be divided into two distinct categories: supramolecular homosynthons and supramolecular heterosynthons.82 Supramolecular homosynthons

occur as a consequence of the interaction between identical, complementary functional

group as in the case of the carboxylic acid dimer 83-84 (Figure 1.2a) and the amide dimer.

85 Supramolecular heterosynthons result from the interaction between different but

complementary functional groups. Examples of supramolecular heterosynthons include:

carboxylic acid···pyridine 82, 86-98 (Figure 1.2b), alcohol···pyridine 99-120 and carboxylic

acid···amide. 121-130

Figure 1.2 Examples of supramolecular synthons: a) carboxylic acid homosynthon and b) carboxylic acid···pyridine heterosynthon

5 Supramolecular homosynthons typically exist in single component crystals, even though their existence has also been observed in several crystals containing two different carboxylic acids.131-134 However when competing or multiple functional groups are

present the formation of the supramolecular heterosynthon is more likely. Furthermore, if

supramolecular heterosynthons form preferentially the knowledge can be utilized to

design and ultimately generate multi-component crystals of structurally more complex

molecules such as active pharmaceutical ingredients (API’s). General trends observed in a series of relevant crystal structures, in terms of the prevalence of specific supramolecular synthons as compared to others, would therefore provide valuable insight for crystal engineering strategies toward the generation of novel multiple-component crystals.

Analysis of existing crystal structures represents the first step in a crystal engineering experiment. As such, “the systematic analysis of large numbers of related structures is a powerful research technique, capable of yielding results that could not be obtained by any other method.” 135 This is facilitated by the Cambridge Structural

Database (CSD). The CSD is a depository of crystal structures of over 403,790 organic

and organometallic compounds (ConQuest v1.9, January 2007 update) and has earned its

status as one of the most invaluable research tools in crystal engineering. The wealth of

crystal structures archived within has aided the evolution of the field by allowing the supramolecular retrosynthesis 136 of numerous non-covalent contacts. This has facilitated

the characterization of robust and reliable synthons and the potential for the elucidation of new or perhaps overlooked interactions from existing structures.

6 Etter et al proposed several hydrogen bonding rules, one of which states: “the best

hydrogen-bond donor and the best hydrogen-bond acceptor will preferentially form

hydrogen bonds to one another”. 78, 137 The Etter rules describe anticipated hydrogen patterns for several well studied functional groups and have been used as a working

model for the hierarchal application of these rules to the non-covalent synthesis of

supramolecular structures.

Attempts to classify hydrogen bonded motifs were also addressed by Etter based

upon a system of graph-set notation. 138 Hydrogen bonded patterns are described as

chains (C), dimers (D), rings (R), or intramolecular hydrogen bonds (S). The number of

donors (d) and acceptors (a) used in each motif are assigned as subscripts and superscripts respectively and the number of atoms involved in the pattern is indicated in

2 parenthesis. For example, R 2(8) graph set notation denotes an eight-membered ring with

two hydrogen bond acceptors and two hydrogen bond donors, and is exemplified by the

carboxylic acid dimer (Fig 1.2a). The utility of the graph-set notation lay in the

evaluation of the frequency of a given hydrogen bonding pattern. However, information

with respect to the types of proton donors and proton acceptors engaged in the pattern are not provided. Therefore the frequency of supramolecular synthon composed of specific hydrogen bond donors and acceptors can not be addressed via the graph-set notation system.

The identification of reliable supramolecular synthons is the preliminary step in the design and analysis of multi-component crystal structures and is one of the foci of the

research presented herein.

7 1.1.5. Co-Crystal

The term and the definition of co-crystal is a subject of topical debate. 139-141

Broad definition such as that given by Dunitz defines a co-crystal as “a crystal containing two or more components together.”140 This definition includes molecular adducts, salts, solvates/hydrates, inclusion compounds, etc. More specific perspective taken by others

142-43 describes a co-crystal as “a multiple component crystal formed between compounds

that are solid under ambient conditions… at least one component is molecular and forms

a supramolecular synthon with the remaining components. That all components of a co-

crystal (co-crystal formers) are solids under ambient conditions has important

implications with respect to the stability of the co-crystal and its susceptibility for

preparation in the solid-state. Analysis of the literature, reveal that co-crystals have been

encountered under various terminologies, such as molecular compounds, 144 organic

molecular compounds, 145 addition compounds, 146 molecular complexes, 147 and solid-

state complexes.148 The prototypal co-crystal quinhydrone formed between hydroquinone

and quinone was first reported in 1844 by Wöhler149 however the crystal structure was not elucidated until the 1960’s.150-151

Figure 1.3. Crystal structure of quinhydrone

8 Although long known, co-crystals represent a relatively unexplored class of

compounds as compared to single component crystals or solvates. There are ca. 1,722

hydrogen bonded molecular co-crystals (comprised of components that are solid at room

temperature) which constitute less than 0.5% of all structures archived in the CSD, as

compared to 42,589 hydrates (ca. 11%). However, based upon the increasing number of

relevant literature, it is clear that there is ever-growing interest.

180

160

140

120

100

Frequency 80

0 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 Year

Figure 1.4. Hydrogen bonded co-crystal structures in the CSD from 1985-2005

The inherent physical properties of a molecule in part depend on its crystal structure. Towards this end the generation of multiple component crystals is therefore of great importance. Moreover, co-crystals by nature are composed of two or more component therefore the exploration of the competition occurring between supramolecular synthons may be afforded. As will become evident the CSD can be used to study the competition between supramolecular homosynthon and supramolecular heterosynthon. However there is not enough information to address the hierarchy of

9 supramolecular heterosynthons in a competitive environment. Systematic studies

involving the competition between three hydrogen bonded moieties have only been

undertaken in a few instances. 152-154 Competitive studies by Aakeröy et al. focused on

three distinct hydrogen bonding moieties: primary amide, pyridine, and carboxylic acid.

The study involved co-crystals of iso-nicotinamide and a range of aromatic and aliphatic

acids. The generated co-crystals revealed consistent hydrogen bonding patterns

comprised of two robust supramolecular synthons: carboxylic acid···pyridine heterosynthon and self-complementary primary amide homosynthon. The reproducibility of the hydrogen bonded motifs suggests a dominant tendency of formation of the acid···pyridine heterosynthon over the acid···amide heterosynthon, that is formed in acid and amide-containing compounds in the absence of pyridines. Studies conducted by Bis et al involved alcohol, cyano and aromatic nitrogen moieties. The study involved determining the relative tendency of formation of alcohol-aromatic nitrogen supramolecular heterosynthon in the presence of competing cyano group. It was found that the alcohol-aromatic nitrogen heterosynthon occurred reliably in the presence of the

cyano moiety.

1.1.6. Preparation of Co-Crystals

Co-crystals are usually prepared by evaporation from a solution containing

stoichiometric amounts of components (co-crystal formers). However sublimation,

blending of powders, sonication, growth from melt, slurries and grinding of the

components together are suitable methodologies. Grinding 155-160 or milling of solids is

usually carried out manually using a mortar and pestle or mechanochemically using a ball

10 mill or a Wig L Bug®. Variables that arise are in the control of reaction conditions such

as pressure exerted by the operator or the machine, grinding time and temperature. The

aforementioned technique has profound implications with respect to green chemistry161

which seeks to reduce and prevent pollution via implementation of environment-friendly

chemical processes. Solvent drop grinding 162-163 also referred to as kneading164 or more recently as liquid assisted grinding 165-166 is another promising method of preparation in

which a small amount of suitable solvent is added to the ground mixture in order to accelerate co-crystallization. Jones et al., have successfully shown that the addition of a small quantity of solvent enhances the kinetics of the solid state co-crystallization of cis,cis,cis-1, 3, 5-cyclohexanetricarboxylic acid with pyridyl based molecules.167 Solvent- drop grinding has also been utilized in promoting selective polymorph transformation and for polymorph control.168 The role of the solvent is suggested to act as a lubricant for

molecular diffusion, a sort of ‘solvent catalysis’ for the solid-state process, 164 as well as

enhancing the opportunity for molecular collision. 164

A number of factors contribute to the successful synthesis and isolation of a co-

crystal. A detailed understanding of the supramolecular chemistry of the functional

groups present is a prerequisite for designing a co-crystal since it facilitates the

appropriate selection of co-crystal formers. However when multiple functional groups are

present in a molecule, as is often the case with API’s, the CSD rarely contains enough information to address the hierarchy of supramolecular synthons. Solvent can also be critical in obtaining a particular co-crystal from solution and the relative solubilities of the components in a particular solvent also needs to be considered. Moreover, the role of

11 solvent in the nucleation process remains somewhat poorly understood even though strides are being made in this area. 169

The inherent change in physicochemical properties as a consequence of the

introduction of another component into the crystal lattice and the existence of

supramolecular synthons affords many potential applications of co-crystals. Notable

applications of co-crystals include: non-covalent derivatization, a term that was coined in

the context of modifying the stability of Polaroid film 73 and the considerable interest

these compounds have attracted with respect to pharmaceuticals.74-75, 129-130, 142, 170, 193-195

Co-crystals have also found applications in solid-state solvent free synthesis116, 171, the formation of biomolecular complexes172 and may potentially act as precursors to the

formation of 2D and 3D polymers. Moreover a recent publication reports that a variety of supramolecular synthons present within the co-crystal may act as precursors to a number of solid state condensation reactions thereby affording solid state synthesis of organic molecules.173

The main emphasis of the research presented herein however focuses upon the

application of co-crystals towards the generation of pharmaceutical co-crystals and

developing strategies to accomplish this goal.

1.1.7. Pharmaceutical Co-Crystals

Undesirable physicochemical properties, physiological barriers, or issues of toxicity often limit the therapeutic benefit of drugs. This has motivated research in API form optimization and drug delivery systems for poorly soluble and poorly absorbed

substances. For orally administered drugs, unless the substance has an aqueous solubility

12 above 10 mg/ml over pH-range 1-7 potential absorption problems may occur. The

European Pharmacopoeia reports that more than 40% of drug substances have aqueous solubility below 1 mg/ml. The primary method presently utilized in enhancing dissolution of these ‘low solubility’ substances is the selection of a salt form for weak acids and bases 174-176 or covalent modification. An apparently overlooked means to improve drug dissolution until recently is to make benefit of the reactive functionalities in the molecule and their interactions by hydrogen bonding.

Crystalline self-assemblies provide a promising modality for improving physicochemical properties such as drug solubility, physical stability, dissolution rate and bioavailability. The emergence of crystal engineering and the supramolecular design approach to modify APIs extends to these issues without changing the pharmacological benefit of the API. Traditional crystalline forms of APIs have been limited to salts, hydrates/solvates, polymorphs and the free acid or base form. 177 Hydrates/solvates are typically obtained as a result of adventitious uptake of water/solvent upon crystallization and like polymorphs they are difficult to be rationally designed. The possibility of dehydration/desolvation and subsequent formation of amorphous material, that may occur as a function of time and storage conditions is also a concern.

Pharmaceutical co-crystals are multiple component crystals that are formed between an API and at least one or more co-crystal former that are solids under ambient conditions.74 This class of compound has gained much interest over the past few years since they offer the potential to amend undesirable physicochemical properties without covalent modification of the API. Moreover unlike salt forms of API’s, co-crystal formation is not restricted to an ionizable (acidic or basic) center on the API and can

13 simultaneously address multiple functional groups on the API. A relative large number of

non-toxic compounds with hydrogen bonding functionalities exist on the GRAS

(generally regarded as safe) list that may act as co-crystal formers in comparison to the limited number of salt forming counter-ions in use.174

The presence of multiple functional groups inherent to APIs affords the opportunity for the design of pharmaceutical co-crystals. In fact an analysis of the top

100 prescription drugs178 reveal that 39% of pharmaceutically active ingredients contains at least one alcohol and 30% contain at least one carboxylic acid, this is also consistent with the percentage alcohol and carboxylic acid moieties in the Merck Index.179

Consequently addressing the ability of these functional groups to form supramolecular

synthons would be of great interest.

Table 1.2 Percentage Occurrence of hydrogen bonding functional groups in APIs

Functional Top 100 Group Prescription CSD only Drugs Organics % % Alcohol 39 20 3º amine 37 11 Carbonyl 35 14 Ether 33 27 2° amine 31 7 Carboxylic acid 30 6 Ester 22 20 Aromatic N 12 6 2° amide 11 9 Sulfonamide 3 1

Analysis of the 1722 co-crystals deposited in the CSD reveal that approximately

5% contain API molecules.180-192 Whereas, some of the examples are a result of 14 serendipity, the first crystal engineered series of pharmaceutical co-crystals may be

attributed to works of Caira et al involving the complexation of sulfonamide drugs193-195 and the extensive research of Whitesides et al. concerning supramolecular assemblies of barbiturates and melamine derivatives. 196-199

Figure 1.5. Co-crystal of sulfadimidine and acetylsalicylic acid, VUGMIT

Figure 1.6. Co-crystal of barbital and N,N’-bis(m-tolyl)melamine JICVIA10, sustained by 3-point recognition supramolecular heterosynthon

The crystal engineering approach to APIs based upon the use of reliable

supramolecular heterosynthons is exemplified by several series of co-crystals involving

carbamazepine (CBZ),129-130 ibuprofen,82 piracetam,200 fluoxetine hydrochloride201 and itraconazole.202 CBZ had four reported polymorphs and two solvates. All forms of CBZ

15 for which structural data was available were sustained by the primary amide dimer

(Fig 1.7.) and the peripheral H-bond donors and acceptor pairs remained unused.

Figure 1.7. Crystal structure of carbamazepine sustained by amide dimer

Two strategies based upon information obtained from a CSD analysis of the primary amide functional group was employed in designing co-crystals of CBZ. Strategy

1, involved breaking the amide dimer via the introduction of a carboxylic acid moiety thereby, forming the acid-amide supramolecular heterosynthon and strategy 2, utilized the peripheral NH2 H-bonding sites while keeping the amide dimer intact. The acid- amide supramolecular heterosynthon exists in 47% of entries that contain both an acid and an amide. Both strategies were successfully implemented to generate several co- crystals of CBZ.

Figure 1.8. Illustrate the co-crystal of carbamazepine • acetylsalicylic acid sustained by the two point recognition acid-amide supramolecular heterosynthon.

Figure 1.9. Crystal structure of (carbamazepine.)2●4,4’-dipyridyl illustrates the intact amide dimer and H-bonding of 4,4’-dipyridyl to the peripheral N-H.

17 Although we are unaware of any pharmaceutical co-crystals that have been approved by the FDA, there have been several reports related to their physicochemical properties. The CBZ•saccharin co-crystal exhibits improved dissolution, chemical

suspension and, bioavailability to that of the parent compound.203 Moreover based upon

1,200 high throughput screening experiments the co-crystal also appears to lack the

relative propensity towards polymorphism as is seen in pure CBZ. 203

Figure 1.9. The crystal structure of carbamazepine●saccharin co-crystal

2-[4-(4-chloro-2-flourophenoxy)phenyl]pyrimidine-4-carboxamide is a sodium

channel blocker with indications in the treatment or prevention of surgical, chronic or neuropathic pain. The glutaric acid• 2-[4-(4-chloro-2-flourophenoxy)phenyl]pyrimidine-

4-carboxamide co-crystal exhibits 18 fold greater intrinsic dissolution rate as compared to the parent API in a single dose dog exposure study.204 The co-crystal was also physically

and chemically stable for storage under stress conditions of 40°C/75% relative humidity

and 60°C for 2 months.

Figure 1.11. Illustrates the hydrogen bonding interaction present in 2-[4-(4-chloro-2- flourophenoxy)phenyl]pyrimidine-4-carboxamide•glutaric acid co-crystal

Theophylline, a drug used in the treatment of respiratory illnesses such as asthma, is known to convert between the crystalline anhydrate and the monohydrous form as a function of relative humidity (RH). This represents a challenge in the formulation process. A series of dicarboxylic acid co-crystals of theophylline were subjected to relative humidity changes in an effort to evaluate their stability in relation to crystalline theophylline.205 None of the co-crystals in the study converted into a hydrated form upon storage at high humidity. Moreover the theophylline•oxalic acid co-crystal demonstrated superior humidity stability as compared to anhydrous theophylline and the other co- crystals exhibited comparable stability to the theophylline anhydrate. Similar studies involving a series of co-crystals of caffeine and dicarboxylic acids have also been undertaken.206 The relative stability profiles of the co-crystals differed from that of the crystalline caffeine in that no co-crystal hydrate was found. Moreover the co-crystals that were unstable relative to RH dissociated into starting components.

Dissolution studies of pharmaceutical co-crystals of itraconazole, a highly water insoluble antifungal drug, with 1,4-dicarboxylic acids, indicate that the co-crystals achieve and sustain 4 to 20-fold higher concentrations as compared to the crystalline itraconazole. 202 19

Figure 1.10. Crystal structure of cis-itraconazole●succinic acid co-crystals

A recent study involving co-crystals of fluoxetine hydrochloride (Prozac) an anti-

depressant, with several pharmaceutically acceptable carboxylic acids illustrates the

dependence of the co-crystal on the aqueous solubility of the utilized co-crystal former.201

Consequently it is possible to fine-tune the dissolution rate the API. Additionally the

solubility of the fluoxetine hydrochloride•succinic acid co-crystal is doubled as compared

to the fluoxetine hydrochloride salt.

Figure 1.11. The crystal structure of fluoxetine hydrochloride•succinic acid co-crystal sustained by charge assisted carboxylic acid⋅⋅⋅Cl- interactions

L-883555 is a phosphodiesterase IV inhibitor with indication in the treatment of asthma and chronic obstructive pulmonary disease. Non-stoichiometric, isostructural

20 complexes of L-883555 and L-tartaric acid demonstrated much higher bioavailability in rhesus monkeys as compared to the free base form of L-883555. 207 In particular the 2:1

co-crystal of L-883555•L-tartaric acid exhibited better physical properties and was

chosen as the viable solid form for safety assessment.

The aforementioned studies illustrate the potential impact of pharmaceutical co-

crystals on the pharmaceutical industry in terms of both form and properties.

1.1.8. Polymorphism

Polymorphism can be defined as the existence of more than one crystal structure

of the same compound.208-210 This phenomenon was recognized as early as 1822.211

Polymorphs arise as a consequence of different arrangements and/ or conformation of the same molecules in the crystal lattice and as such are classified primarily as structural or conformational polymorphs. The possibility of homosynthons or heterosynthons, the formation of n-point recognition, as well as slight changes in torsion angles are factors that can lead to the phenomenon of polymorphism. The topical issue of polymorphism is now recognized as being a major scientific challenge quite apart from its chemical and legal implications in the pharmaceutical industry.

Polymorphs may differ in packing, spectroscopic, thermodynamic, kinetic, surface and mechanical properties. The polymorphic form that crystallizes from solution depends on an inter-play of several factors. The factors include polarity of solvent, initial supersaturation and depending on the crystallization method, the rate of cooling or the evaporation of the solvent. Impurities can also affect the potential for a polymorph crystallizing from solution.

21 The inability to predict the existence of polymorphs or crystal structures in

general, has important intellectual property and scientific implications. For example, the

appearance of an undesired polymorph can invoke problems during the formulation

process and lead to patent litigations.209, 212 On the other hand, a novel polymorph can

offer an opportunity in terms of improved physicochemical properties and product

development. Furthermore, since physicochemical properties of a compound can differ critically from one form to another, inducing and controlling a specific polymorph is of utmost importance.

Polymorphism in organic compounds is perhaps exemplified by 5-methyl-2-(2- nitrophenyl)amino] 3-thiophenecarbonitrile (ROY), which has been crystallized as seven polymorphic modifications.213-215 The system has been named ROY because to its red, orange and yellow crystal colors. The forms crystallize as yellow prisms, red prisms, orange needles, orange plates, yellow needles, orange red plates and red plates.

From a pharmaceutical perspective the stability of the product, the ability to process and bioavailability are influenced by the physicochemical properties of the varied solid state forms. 216 The impact of polymorphism on drug behavior is perhaps illustrated by chloramphenicol palmitate (CAPP). CAPP is a broad-spectrum antibiotic known to crystallize in at least three polymorphic forms; and one amorphous form.217-218 The most

stable form, A, is marketed. Form B, however, has an eightfold higher bioactivity than

form A, creating the danger of fatal dosages when the unwanted polymorph is

unwittingly administered because of alterations in process or storage conditions. 218

The impact of polymorphism with intellectual property implications is exemplified by the case of ranitidine hydrochloride.219 GlaxoSmithKline entered a

22 lengthy court case against Novopharm for alleged patent infringement based on its right

to manufacture and market a different polymorphic form of Glaxo’s best-selling anti- ulcer drug, Zantac. The polymorphic forms in question were therapeutically equivalent.

The existence of polymorphism implies that kinetic factors are important during

nucleation and growth and that the free energy differences between the different

crystalline forms are small (<10KJmol-1). The phenomenon is still not entirely

understood, however, recent literature reveal that the solvent-drop grinding approach can

be utilized as an efficient method to achieve selective transformations between specific

polymorphs.168

1.1.9. Summary

The research presented herein focuses on crystal engineering of co-crystals and

pharmaceutical co-crystals. Particular emphasis is placed upon the exploration of co-

crystals in the context of: delineation of the reliability of hydrogen bonded

supramolecular synthons and their hierarchies; exploring the viability of alternatives to

solution based methods of preparation of co-crystals specifically melts, grinding and

solvent drop grinding; and evaluation of the susceptibility of co-crystals towards

polymorphism using the solvent-drop grinding technique. The rational design and

synthesis of pharmaceutical co-crystals accomplished by the judicious selection of co-

crystal formers facilitated by analysis of existing crystals structures in the CSD will be

demonstrated. The processing of pharmaceutical co-crystals will also be addressed in

terms of slurry conversion, solvent drop grinding and solution crystallization.

23 1.2 References Cited

1. Lehn, J. M., Struct. Bonding, 1973, 16, 1.

2. Lehn, J. M., Pure Appl. Chem. 1978, 50, 871.

3. Lehn, J. M. Science 1985, 227, 849.

4. Lehn, J. M.; Atwood, J. L.; Davies, J. E. D.; MacNicol, D. D.; Vögtle, F.

Comprehensive Supramolecular Chemistry; Pergamon: Oxford, 1996.

5. Vögtle, F. Supramolecular Chemistry; Wiley, J.: New York, 1991.

6. Lehn, J. M. Supramolecular Chemistry: Concepts and Perspectives; VCH:

Weinheim, 1995.

7. Steed, J. W.; Atwood, J. L. Supramolecular Chemistry, Wiley, J.; Chichester,

2000.

8. Curtis, N. F.; House, D. A. Chemistry & Industry, 1961, 708.

9. Caulder, D. L.; Raymond, K. N. Acc. Chem. Res., 1999, 32, 975.

10. Curry, J. D.; Busch, D. H. J. Am. Chem. Soc., 1964, 86, 592.

11. Jager, E.-G. Z. Chem., 1964, 4, 437.

12. Antonisse, M. M. G.; Reinhoudt, Chem Commun., 1998, 443.

13. Pedersen, C. J. J. Am. Chem. Soc., 1967, 89, 7017.

14. Pedersen, C. J., Angew. Chem. Int. Ed. Engl., 1988, 27, 1021.

15. Cram, D. J.; Dewhirst, K. C. J. Am. Chem. Soc., 1959, 81, 5963.

16. Cram, D. J.; Bauer, R. H. J. Am. Chem. Soc., 1959, 81, 5971.

17. Cram, D. J.; Bauer, R. H.; Allinger, N. L.; Reeves, R. A.; Wechter, W. J.;

Heilbronner, E. J. Am. Chem. Soc., 1959, 81, 5977.

24 18. Cram, D. J. Angew. Chem. Int. Ed. Engl. 1988, 27, 1009.

19. Ehrlich, P. Studies on Immunity; Wiley: New York, 1906.

20. Wolf, K. L.; Wolff, R. Angew. Chem. 1949, 61, 191.

21. Cram, D. J.; Cram, J. M. Science 1974, 183, 803.

22. Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017.

23. Dietrich, B. ; Lehn, J. M.; Sauvage, J. P. Tetrahedron Lett. 1969, 2889.

24. Fischer, E. Ber. Deutsch. Chem. Ges. 1894, 27, 2985.

25. Lehn, J. M. Angew. Chem. Int. Ed. 1990, 29, 1304. 24.

26. Maitland, G. C.; Rigby, E. B.; Smith, E. B.; Wakeham, W. A. Intermolecular

Forces: Their Origin and Determination; Oxford University Press: Oxford, 1981.

27. Jeffrey, G. A. An Introduction to Hydrogen Bonding.; Oxford University Press:

Oxford, 1997.

28. Jeffrey, G. A.; Saenger, W. Hydrogen Bonding in Biological Structures; Springer:

Berlin, 1991.

29. Pauling, L. The Nature of Chemical Bond; Cornell University Press: New York,

1948.

30. Whitesides, G. M.; Simanek, E. E.; Mathias, J. P.; Seto, C. T.; Chin, D. N.;

Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995, 28, 37.

31. Prins, L. J. ; Reinhoudt, D. N.; Timmerman, P. Angew. Chem. Int. Ed. 2001, 40,

2383.

32. Rotello, V. M.; Viani, E. A.; Deslongchamps, G.; Murray, B. A.; Rebek, J. J. Am.

Chem. Soc. 1993, 115, 797.

25 33. Hirschberg J. H. K. K.; Brunsveld, L.; Ramzi, A.; Vekemans Jajm; Sijbesma, R.

P.; Meijer, E. W. Nature 2000, 407, 167.

34. Lehn, J. M.; Mascal, M.; Decian, A.; Fischer, J. J. Chem. Soc. 1990, 479.

35. Amaya, T.; Rebek, J. J. Am. Chem. Soc. 2004, 126, 14149.

36. Biros, S. M.; Ullrich, E. C.; Hof, F.; Trembleau, L.; Rebek, J. J. Am. Chem. Soc.

2004, 126, 2870.

37. Karle, I. L.; Ranganathan, D.; Haridas, V. J. Am. Chem. Soc. 1997, 119, 2777.

38. Zafar, A.; Geib, S. J.; Hamuro, Y.; Carr, A. J.; Hamilton, A. D. Tetrahedron 2000,

56, 8419.

39. Yang, J.; Fan, E. K.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1993, 115,

5314.

40. Rebek, J. Angew. Chem., Int. Ed. Engl. 1990, 29, 245.

41. Murray, T. J.; Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114, 4010.

42. Fan, E.; Vanarman, S. A.; Kincaid, S.; Hamilton, A. D. J. Am. Chem. Soc. 1993,

115, 369.

43. Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.

44. Metrangolo, P.; Resnati, G. Chem. Eur. J. 2001, 7, 2511-2519.

45. Metrangolo, P.; Neukirch, H.; Pilati, T.; Resnati, G. Acc. Chem. Res. 2005, 38,

386-395.

46. Guthrie, F., J. Chem Soc., 1863, 16, 239.

47. Remses I., J. F., Am. Chem. J. 1896, 18, 90.

48. Hassel, O.; Stromme, K. O. Nature, 1958, 182, 1155.

26 49. Pennington, William T.; Harris, Jeffrey L.; Hanks, Timothy W Abstracts of

Papers, 225th ACS National Meeting, New Orleans, LA, United States, March

23-27, 2003, INOR-598.

50. Bailey, Rosa D.; Grabarczyk, M.; Hanks, T. W.; Pennington, William T. J.

Chem. Soc., Perkin Trans. 2, 1997, 2781.

51. Crihfield, A.; Hartwell, J.; Phelps, D.; Walsh, R. B.; Harris, J. L.; Payne, J. F.;

Pennington, W. T.; Hanks, T. W. Crystal Growth Des. 2003, 3, 313.

52. Walsh, R. B.; Padgett, C. W.; Metrangolo, P.; Resnati, G.; Hanks, T. W.;

Pennington, W. T. Crystal Growth Des. 2001, 1, 165.

53. Cardillo, P.; Corradi, E.; Lunghi, A.; Valdo Meille, S.; Messina, T. M.;

Metrangolo, P.; Resnati, G. Tetrahedron, 2000, 56, 5535.

54. Romaniello, P.; Lelj, F. J. Phys. Chem. A. 2002, 106, 9114.

55. Metrangolo, P.; Resnati, G.; Pilati, T.; Liantonio, R.; Meyer, F. J. Polymer

Science, 2006, 2007, 45, 1.

56. Saha, B. K.; Nangia, A.; Jaskolski, M. CrystEngComm, 2005, 7, 355.

57. Metrangolo, P.; Pilati, T.; Resnati, G. CrystEngComm, 2006, 8, 946.

58. Guardigli, C.; Liantonio, R.; Lorenza Mele, M.; Metrangolo, P.; Resnati, G.;

Pilati, T. Supramolecular Chemistry, 2003, 15, 177.

59. Neukirch, H.; Guido, E.; Liantonio, R.; Metrangolo, P.; Pilati, T.; Resnati, G.

Chem. Commun., 2005, 1534.

60. Dunitz, J. D. The Crystal as a Supramolecular Entity.; Desiraju, G.R.; Ed.; John

Wiley and Sons: Chichester, 1996.

61. Gdanitz, R. J. Curr. Op. Solid State Mater. Sci. 1998, 3, 414.

27 62. Gavezzotti, A. Acc. Chem. Res. 1994, 27, 309.

63. Ball, P. Nature 1996, 381, 648.

64. Desiraju, G. R. Nature Mater. 2002, 1, 77.

65. Dunitz, J. D. Chem. Commun. 2003, 545.

66. Lommerse, J. P. M.; Motherwell, W. D. S.; Ammon, H. L.; Dunitz, J. D.;

Gavezzotti, A.; Hofmann, D. W. M.; Leusen, F. J. J.; Mooij, W. T. M.; Price, S.

L.; Schweizer, B.; Schmidt, M. U.; Van Eijck, B. P.; Verwer, P.; Williams, D. E.

Acta Crystallogr. B 2000, 56, 697.

67. Gavezzotti, A.; Filippini, G. J. Am. Chem. Soc. 1995, 117, 12299.

68. Motherwell, W. D. S.; Ammon, H. L.; Dunitz, J. D.; Dzyabchenko, A.; Erk, P.;

Gavezzotti, A.; Hofmann, D. W. M.; Leusen, F. J. J.; Lommerse, J. P. M.; Mooij,

W. T. M.; Price, S. L.; Scheraga, H.; Schweizer, B.; Schmidt, M. U.; Van Eijck,

B. P.; Verwer, P.; Williams, D. E. Acta Crystallogr. B 2002, 58, 647.

69. Day, G. M.; Motherwell, W. D. S.; Ammon, H. L.; Boerrigter, S. X. M.; Della

Valle, R. G.; Venuti, E.; Dzyabchenko, A.; Dunitz, J. D.; Schweizer, B.; Van

Eijck, B. P.; Erk, P.; Facelli, J. C.; Bazterra, V. E.; Ferraro, M. B.; Hofmann, D.

W. M.; Leusen, F. J. J.; Liang, C.; Pantelides, C. C.; Karamertzanis, P. G.; Price,

S. L.; Lewis, T. C.; Nowell, H.; Torrisi, A.; Scheraga, H. A.; Arnautova, Y. A.;

Schmidt, M. U.; Verwer, P. Acta Crystallogr. 2005, B61, 511.

70. Desiraju, G. R. Crystal Engineering: the Design of Organic Solids; Elsevier:

Amsterdam, 1989.

71. Panunto, T. W.; Urbanczyk-Lipkowska, Z.; Johnson, R.; Etter, M. C. J. Am.

Chem. Soc. 1987, 109, 7786.

28 72. Russell, V. A.; Evans, C. C.; Li, W. J.; Ward, M. D. Science 1997, 276, 575.

73. Taylor, L. D.; Warner, J. C. US 5338644 A 19940816 Cont. of US 5,177,262.

74. Zaworotko, M. J. Cryst. Growth Des. 2007, 7, 4.

75. Almarsson, Ö.; Zaworotko, M. J. Chem. Commun. 2004, 1889.

76. Pepinsky, R. Phys. Rev. 1955, 100, 971.

77. Schmidt, G. M. Pure Appl. Chem. 1971, 27, 647.

78. Etter, M. C. Acc. Chem. Res. 1990, 23, 120.

79. Desiraju, G. R. Angew. Chem. Int. Ed. 1995, 34, 2311.

80. Allen, F. H. ; Kennard, O. Chem. Des. Autom. News 1993, 8, 31.

81. Allen, F. H.; Motherwell, W. D. S.; Raithby, P. R.; Shields, G. P.; Taylor, R. New

J. Chem. 1999, 23, 25.

82. Walsh, R. D. B.; Bradner, M. W.; Fleischman, S.; Morales, L. A.; Moulton, B.;

Rodríguez-Hornedo, N.; Zaworotko, M. J. Chem. Commun. 2003, 186.

83. Leiserowitz, L. Acta Crystallogr. 1976, B32, 775.

84. Etter, M. C. J. Am. Chem. Soc. 1982, 104, 1095.

85. Leiserowitz, L.; Schmidt, G. M. J. J. Chem. Soc. 1969, 2372.

86. Krishnamohan Sharma, C. V.; Zaworotko, M. J. Chem. Commun., 1996, 2655.

87. Arora, K. K.; Pedireddi, V. R. J.Org. Chem., 2003, 68, 9177.

88. Smolka, T.; Schaller, T.; Sustmann, R.; Blaser, D.; Boese, R. J. Prakt. Chem.,

2000, 342, 465.

89. Olenik, B.; Smolka, T.; Boese, R.; Sustmann, R. Cryst. Growth Des. 2003, 3, 183.

90. Shan, N.; Bond, A. D.; Jones, W. Cryst. Eng., 2002, 5, 9.

91. Chatterjee, S.; Pedireddi, V. R.; Rao, C. N. R. Tet. Lett., 1998, 39, 2843.

29 92. Zhang, J.; Wu, L.; Fan, Y. J. Mol. Struct., 2003, 660, 119.

93. Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. J. Am. Chem. Soc. 2002, 124,

14425.

94. Batchelor, E.; Klinowski, J.; Jones, W. J. Mater. Chem., 2000, 10, 839.

95. Shan, N.; Batchelor, E.; Jones, W. Tet. Lett., 2002, 43, 8721.

96. Bhogala, B. R.; Vishweshwar, P.; Nangia, A. Cryst. Growth Des. 2002, 2, 325.

97. Bond, A. D. Chem. Commun. 2003, 250.

98. Etter, M. C.; Adsmond, D. A. J. Chem. Soc. 1990, 589.

99. Jayaraman, A.; Balasubramaniam, V.; Valiyaveettil, S. Cryst. Growth Des.

2006, 6, 150.

100. Aitipamula, S.; Nangia, A.; Thaimattam, R.; Jaskolski, M. Acta Crystallogr.,

2003, C59, o481.

101. Thalladi, V. R.; Smolka, T.; Boese, R.; Sustmann, R CrystEngComm , 2000, 2,

96.

102. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr.,

1999, C55, 2133.

103. Lough, A. J.; Gregson, R. M.; Ferguson, G.; Glidewell, C. Acta Crystallogr.,

1999, C55, 1890.

104. Lavender, E. S.; Ferguson, G.; Glidewell, C. Acta Crystallogr., 1999, C55, 430.

105. Zeng, Q.; Wu, D.; Wang, C.; Ma, H.; Lu, J.; Liu, C.; Xu, S.; Li, Y.; Bai, C.

Cryst. Growth Des., 2005, 5, 1889.

106. Friscic T.; MacGillivray L. R Chem. Commun., 2003, 1306.

107. Friscic T.; Drab, D. M.; MacGillivray, L. R. Organic letters, 2004, 6, 4647.

30 108. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr.,

1999, C55, 2133.

109. Lavender, E. S.; Ferguson, G.; Glidewell, C. Acta Crystallogr., 1999, C55, 430.

110. Ferguson, G.; Glidewell, C.; Lavender, E. S. Acta Crystallogr., 1999, B55, 591.

111. Sokolov, A. N.; Friscic, T.; MacGillivray, L. R. J. Am. Chem. Soc., 2006, 128,

2806.

112. Smolka, T.; Boese, R.; Sustmann, R. Structural Chemistry, 1999, 10, 429.

113. Oswald, I. D. H.; Motherwell, W. D. S.; Parsons, S. Acta Crystallogr., 2005, B61,

46.

114. Bis, J. A.; Vishweshwar, P.; Middleton, R. A.; Zaworotko, M. J. Cryst. Growth

Des., 2006, 6, 1048.

115. Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Molecular

Pharmaceutics, 2007, 4, 401.

116. Macgillivray, L. R.; Reid, J. L.; Ripmeester, J.A.; J. Am. Chem. Soc., 2000, 122,

7817.

117. Ma, B. q.; Zhang Y.; Coppens, P. Cryst. Growth Des. 2002, 2, 7.

118. Vishweshwar, P.; Nangia, A.; Lynch, V. M. CrystEngComm 2003, 5, 164.

119. Papaefstathiou, G. S.; MacGillivray, L. R. Org. Lett. 2001, 3, 3835.

120. Haung, K, -S.; Britton, D.; Etter, M. C.; Byrn S.R. J. Mater. Chem., 1997, 7, 713.

121. Aakeroey, C. B.; Beatty, A. M.; Helfrich, B. A.; Nieuwenhuyzen, M. Cryst.

Growth Des., 2003, 3, 159.

122. Aakeroy, C. B.; Desper, J.; Helfrich, B. A. CrystEngComm., 2004, 6, 19..

31 123. Aakeroy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem., Int. Ed. 2001, 40,

3240.

124. Aakeroy, C. B.; Desper, J.; Elisabeth, E.; Helfrich, B. A.; Levin, B.; Urbina, J. F.

Zeit. fuer Kristallogr., 2005, 220, 325.

125. Edwards, M. R.; Jones, W.; Motherwell, W. D. S. CrystEngComm, 2006, 8, 545.

126. Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des., 2003, 3, 783.

127. Leiserowitz, L.; Nader, F. Acta Crystallogr. 1977, 33, 2719.

128. Videnova-Adrabinska, V.; Etter, M. C. J. Chem. Crystallogr. 1995, 25, 823.

129. Fleischman, S. G.; Kuduva, S. S.; McMahon, J. A.; Moulton, B.; Walsh, R. D.

B.; Rodríguez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des. 2003, 3, 909.

130. McMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.; McLaughlin, O. L.;

Zaworotko, M. J. Z. Kristallogr. 2005, 220, 340.

131. Goud, B. S.; Reddy, P. K.; Panneerselvam, K.; Desiraju, G. R. Acta Crystallogr.

1995, C51, 683.

132. Desiraju, G. R.; Sarma, J. A. R. P. J. Chem. Soc. 1983, 45.

133. Aakeröy, C. B.; Desper, J.; Helfrich, B. A. CrystEngComm 2004, 6, 19.

134. Vishweshwar, P.; Beauchamp, D. A.; Zaworotko, M. J. Cryst. Growth Des.,

2006, 6, 2429.

135. Allen, F. H.; Allen, Frank H.; Shields, Gregory P.; Taylor, R.; Raithby, P. R.

Chem. Commun., 1998, 1043.

136. Desiraju, G. R. ed. The Crystal as a Supramolecular Entity: Perspectives in

Supramolecular Chemistry 2, Wiley and Sons, Chichester, 1996.

137. Etter, M. C. J. Phys. Chem. 1991, 95, 4601.

32 138. Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr. B46, 1990, 256.

139. Desiraju, G. R. CrystEngComm, 2003, 5, 466.

140. Dunitz, J. D. CrystEngComm, 2003, 5, 506.

141. Childs, S. L.; Stahly, G. P.; Park, A. Molecular Pharmaceutics, 2007, 4, 323.

142. Almarsson, O; Bourghol Hickey, M.; Peterson, M.; Zaworotko, M. J.; Moulton,

B.; Rodriguez-Hornedo, N. PCT Int. Appl. WO 2004078161, 2004.

143. Aakeröy, C. B.; Salmon, D. J. CrystEngComm, 2005, 7, 439.

144. Ling, A. R.; Baker, J. L. J. Chem. Soc. 1893, 63, 1314.

145. Anderson, J. S. Nature 1937, 140, 583.

146. Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1931, 53, 2784.

147. Vanniekerk, J. N.; Saunder, D. H. Acta Crystallogr., 1948, 1, 44.

148. Hall, B.; Devlin, J. P. J. Phys. Chem. 1967, 71, 465.

149. Wöhler F. Annalen 1844, 51, 153.

150. Sakurai. Acta Crystallogr. 1965, 19, 320.

151. Sakurai, T. Acta Crystallogr. 1968, B 24, 403.

152. Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. J. Am. Chem. Soc. 2002, 124,

14425.

153. Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2003, 3, 783

154. Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Molecular

Pharmaceutics, 2007, 4, 401.

155. Etter, M. C.; Frankenbach, G. M. Chem. Mater. 1989, 1, 10.

156. Etter, M. C.; Frankenbach, G. M.; Bernstein, J. Tetrahedron Lett. 1989, 30, 3617.

33 157. Etter, M. C.; Urbanczyklipkowska, Z.; Ziaebrahimi, M.; Panunto, T. W. J. Am.

Chem. Soc. 1990, 112, 8415.

158. Etter, M. C.; Reutzel, S. M. J. Am. Chem. Soc. 1991, 113, 2586.

159. Etter, M. C.; Reutzel, S. M.; Choo, C. G. J. Am. Chem. Soc. 1993, 115, 4411.

160. Trask, A. V.; Jones, W. Topics in Current Chemistry, 2005, 254, 41.

161. Anastas, P.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford

University Press: London, 1998.

162. Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 2372.

163. Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem. Commun., 2004, 890.

164. Braga, D.; Giaffreda, S .L.; Grepioni, F.; Pettersen, A.; Maini, L.; Curzi, M.;

Polito, M. Dalton Trans., 2006, 1249.

165. Friscic, T.; Fabian, L.; Burley, J. C.; Jones, W.; Motherwell, W. D. S. Chem.

Commun., 2006, 5009.

166. Friscic, T.; Trask, A. V.; Jones, W.; Motherwell, W. D. S. Angew. Chem., Int. Ed.

2006, 45, 7546.

167. Trask, A. V.; Shan, N.; Motherwell, W. D. S.; Jones, W.; Feng, S.; Tan, R. B. H.;

Carpenter, K. J. Chem. Commun., 2005, 880.

168. Shan, N.; Toda, F.; Jones, W. Chem. Commun., 2002, 2372.

169. Rodriquez-Hornendo, N.; Murphy D. J. Pharm. Sci., 1999, 88, 651.

170. Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci.,

2006, 95, 499.

171. MacGillivray, L. R. CrystEngComm, 2002, 4, 37.

34 172. Paul, D.; Suzumura, A.; Sugimoto, H.; Teraoka, J.; Shinoda, S.; Tsukube, H. J.

Am. Chem. Soc., 2003, 125, 11478.

173. Cheney, M. L.; McManus, G. J.; Perman, J. A.; Wang, Z.; Zaworotko, M. J.

Crystal. Growth Des. 2007, 7, 616.

174. Stahl, P. H.; Nakano, M. Pharmaceutical Aspects of the Drug Salt Form, in

Handbook of Pharmaceutical Salts: Properties, Selection, and Use; Ed. Stahl, P.

H. and Wermuth, C. G, Wiley-VCH/VCHA: New York, 2002.

175. Gould, P. L. Int. J. Pharm. 1986, 33, 201.

176. Berge, S. M.; Bighley, L. D.; Monkhouse, D. C. J. Pharm. Sci. 1977, 66, 1.

177. Haleblian, J. K. J. Pharm. Sci. 1975, 64, 1269.

178. Web Page, http://www.rxlist.com/top200.htm

179. Merck Index version. 13.4.

180. 5% API CSD refcodes of 32 co-crystals of barbital: AEPDEB, AMIWUO,

BARAPY10, BARBAM, BARBUR, BARHMP, BARIMZ10, BARMPN,

BIGCUP, CAFBAR20, EADBAR10, HIBJUX, HIBKEI, JICTIY, JICTOE,

JICTUK, JICVAS, JICVEW, JICVIA, JICVOG, JICVUM, JUBRAZ, KEGPUH,

KUFPIK, MUDSAF, MUDSEJ, MUDSIN, PIYGEJ, QQQEUV, QQQFVA,

WETSOD, WETTUK.

181. CSD refcodes of 14 co-crystals of sulfonamide drugs: GEYSAE, SACCAF,

SANAPY, SMZTMP, SORWEB, SORWIF, STHSAM, SULTHE, VIGVOW,

VUGMIT, VUGMOZ, XEXCAE, XEXCEI, YOSMOI.

182. CSD refcodes of 8 co-crystals of phenathiazine: BUNRAD, DAPXUN,

LENGOA, NIWCEB, PHNSNB10, PHTNBA, PTZPMA, PTZTCQ.

35 183. CSD refcodes of 9 co-crystals of carbamazepine: UNEYOB, UNEYKH,

UNEZAO, UNEZES, UNIBIC, TAZRAO, XAQQUC, XAQRAJ, XAQRIR.

184. CSD refcodes of 9 co-crystals of theophylline: CSATEO, DUXZAX, SULTHE,

THOPBA, ZEXTIF, XEJXEQ, XEJXAM, XEJWUF, XEJXIU.

185. CSD refcodes of 6 co-crystals of caffeine: CAFSAL, DIJVOH, DIJVUN,

SACCAF, VIGVOW, EXUQUJ.

186. CSD refcodes of 2 co-crystals of fluribuprofen: HUPPEN, HUPPIR.

187. CSD refcode of the co-crystal of ibuprofen: HUPPAJ.

188. CSD refcode of the co-crystal of itraconazole: IKEQEU.

189. CSD refcode of the co-crystal of diphenylhydantoin: DPHPZL.

190. CSD refcode of the co-crystal of naproxen: YOCZUL.

191. CSD refcodes of 3 co-crystals of fluoxetine hydrochloride: RAJFAK, RAJFEO,

RAJFIS.

192. CSD refcodes of 2 co-crystals of piracetam: DAVPAS, DAVPEW.

193. Caira, M R. J. Chem. Crystallogr., 1994, 24, 695.

194. Caira, M. R. J. Crystallogr. Spectros. Res., 1992, 22, 193.

195. Caira, M. R. J. Crystallogr. Spectros. Res., 1991, 21, 641.

196. Zerkowski, J. A.; MacDonald, J. C.; Whitesides, G. M. Chem. Mater. 1997, 9,

1933.

197. Zerkowski, J. A.; Mathias, J. P.; Whitesides, G. M. J. Am. Chem. Soc. 1994, 116,

4305.

198. Zerkowski, J. A.; Whitesides, G. M. J. Am. Chem. Soc. 1994, 116, 4298.

36 199. Zerkowski, J. A.; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc. 1992, 114,

5473.

200. Vishweshwar, P.; McMahon, J. A.; Peterson, M. L.; Hickey, M. B.; Shattock, T.

R.; Zaworotko, M. J. Chem. Commun., 2005, 4601.

201. Childs S. L.; Chyall L. J.; Dunlap J. T.; Smolenskaya V. N.; Stahly B. C.; Stahly

G. P. J. Am. Chem. Soc. 2004, 126, 13335.

202. Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.;

Guzman, H. R.; Almarsson, Ö. J. Am. Chem. Soc. 2003, 125, 8456.

203. Hickey, M. B.; Peterson, M. L.; Scoppettuolo, L.A.; Morrisette S.L.; Vetter, A.;

Guzman, H.; Remenar, J. F.; Zhang, Z.; Tawa, M. D.; Haley, S.; Zaworotko, M.J.;

Eur. J. Pharm. Biopharm. 2007, accepted manuscript.

204. McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M.

S.; Mannion, R.; O’Donnell, E.; Park, A. Pharm. Res. 2006, 23, 1888.

205. Trask, A. V.; Motherwell, W. D. S.; Jones, W. Int. J. Pharm. 2006, 320, 114.

206. Trask, A. V.; Motherwell, W. D. S.; Jones, W. Crystal Growth Des. 2005, 5,

1013.

207. Variankaval, N.; Wenslow, R.; Murry, J.; Hartman, R.; Helmy, R.; Kwong, E.;

Clas, S.-D.; Dalton, C.; Santos, I. Crystal Growth Des. 2006, 6, 690.

208. McCrone, W. C. Polymorphism. In Physics and Chemistry of the Organic Solid-

State; Interscience: New York, 1965.

209. Bernstein, J. Polymorphism in Molecular Crystals; Clarendon Press: Oxford,

United Kingdom, 2002.

210. Threlfall, T. L. Analyst 1995, 120, 2435.

37 211. Mitscherlich, E. Ann. Chim. Phys. 1822, 19, 350.

212. Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J.

Pharm. Res. 2001, 18, 859.

213. Chen, S.; Guzei, I. A.; Yu, L. J. Am. Chem. Soc. 2005, 127, 9881.

214. Yu, L. Stephenson, G. A.; Mitchell, C. A. Bunnell, C. A.; Snrek, S. V.; Bowyer,

J.; Borchardt, T. B.; Stowell, J. G.; Byrn S. R. J Am. Chem. Soc. 2000, 122, 585.

215. Mitchell, C.A.; Yu, L.; Ward, M.D. J. Am. Chem. Soc. 2001, 123, 10830.

216. Grant D. J. W. Polymorphism in Pharmaceutical Solids: Theory and origin of

polymorphism, Brittain H.G.ed., Marcell Dekker Inc. New York 1999, 1.

217. Kaneniwa, N.; Otsuka, M. Chem. Pharm. Bulletin, 1985, 33, 1660.

218. Bernstein, J. Prog. Clin. Biol. Res. 1989, 289, 203.

219. Wu, V.; Rades, T.; Saville, D. J. Pharmazie, 2000, 55, 508.

2. The Reliability of the Carboxylic Acid-Aromatic Nitrogen Supramolecular

Heterosynthon

2.1. Introduction

Carboxylic acids represent one of the most ubiquitous functional groups in crystal engineering. They possess a hydrogen bond donor as well as an acceptor site and are therefore self complementary. Carboxylic acids are known to self associate to form centrosymmetric dimers I and catemers II.1 A search of the Cambridge Structural

Database (CSD)2-5 reveals that there are 7148 crystal structures that contain at least one carboxylic acid. Of this number 1683 (23%) entries exhibit the acid dimer I whereas 125

(1.7%) crystal structures exhibit the catemer motif II. Based upon the analysis ca. 25% of the total 7148 crystal structures that contain a carboxylic acid are involved in forming either I or II.

O O H O O H

O H O O H O

O H I II

Analysis of the remaining 75% of carboxylic acid containing compounds not involved in forming homosynthon6 I or II reveals that they are engaged in interactions 39 with different complementary functional groups i.e they are involved in forming a variety

of supramolecular heterosynthons.6 Functional groups that were found to interact with

carboxylic acids include: aromatic N (defined in the searches as six membered aromatic

ring containing at least one unprotonated nitrogen), 1° and 2° amides, carbonyls,

phoshonyls, alcohols, chlorides, bromides, etc.

In an effort to further investigate the occurrence of supramolecular homosynthon6

I and II, entries containing carboxylic acids devoid of competing hydrogen bond donors

and/or acceptors were analyzed. There are 452 crystal structures containing at least one

carboxylic acid in the absence of competing functional groups, 422 entries (93 %) exhibit supramolecular homosynthon I as compared to 30 structures (7%) that form supramolecular homosynthon II suggesting that I is favored over II

In this chapter, the presented research is focused on the ability of carboxylic acids and aromatic nitrogen to form reliable carboxylic acid-aromatic nitrogen supramolecular heterosynthon III. In order to form a co-crystal between a carboxylic acid and an

aromatic nitrogen, the basic assumption is that the initial components must engage in the

formation of supramolecular heterosynthon III that can compete successfully with the

carboxylic acid homosynthon, otherwise a mixture of starting material results. The

second part of the study involves evaluating alternative methods such as grinding, solvent

drop grinding7 and melts towards synthesis of co-crystals and to screen the obtained co-

crystals for polymorphism8 using the solvent-drop grind technique. The application of the

knowledge obtained from the series of experiments is the rational design and synthesis of

new multiple-component crystals that contain structurally more complex molecules such as active pharmaceutical ingredients (API’s).

40 2.2. Results and Discussion

A series of mono, di and tricarboxylic acids were co-crystallized with a set of aromatic nitrogen based molecules (Figure 2.1). Single crystal of the following multi- component crystals were isolated: (benzoic acid)2 ● 1,2-bis(4-pyridyl)ethane, 1;

(benzoic acid)2● trans-1,2-bis(4-pyridyl)ethylene, 2; benzoic acid ● 4,4’-bipyridine, 3;

Sorbic acid● 1,2-bis(4-pyridinium)ethane sorbate, 4; (naproxen)2●trans-1,2-bis(4-pyridyl)

ethylene, 5; glutaric acid● 1,2-bis(4-pyridyl)ethane, 6, ; glutaric acid● trans-1,2-bis

(4-pyridyl)ethylene, 7; oxalic acid● tetramethylpyrazine, 8; isophthalic acid● 1,2-bis

(4-pyridyl)ethane, 9; (trimesic acid)2●( trans-1,2-bis(4-pyridyl)ethylene)3, 11 ;

(trimesic acid)2● 1,2-bis(4-pyridyl)ethane)3 Form I, 12a and (trimesic acid)2● 1,2-bis

(4-pyridyl)ethane)3 Form II, 12b

COOH COOH HOOC COOH

HOOC COOH

HOOC COOH glutaric acid benzoic acid isophthalic acid trimesic acid

COOH HOOC COOH COOH HOOC

sorbic acid oxalic acid O naproxen

H3C N CH3 N N N N H3C N CH3

1,2-bis(4-pyridyl)ethane trans-1,2-bis(4-pyridyl)ethylene tetramethylpyrazine (TMP) N 4,4'-bipyridine Figure 2.2.1. Molecular components used in co-crystallization of 1-12

41 2.2.1. CSD Analysis

Searches were conducted using the 2006 release of the CSD using Conquest

version 1.9, with the January 2007 update. Filters placed on the searches include 3D

coordinates determined, R factor < 7.5% and only organics. The visualization package

Mercury 1.5 was used to analyze the retrieved entries.

For each supramolecular synthon considered, initial contact distance well beyond

the sum of the Van der Waals radii of the hydrogen bond donor and the acceptor atoms

were applied. Contact limits for each interaction was subsequently determined from

distance distribution plots. Based on visual inspection of the resulting histogram and

subsequent structural analysis of selected entries, the lower and higher cut offs for hydrogen bonds distances were determined.

In order to distinguish protonated aromatic nitrogen from neutral aromatic nitrogen specific restrictions were applied to the CSD searches. For neutral aromatic nitrogen, the nitrogen atom was defined to be uncharged and the number of bonded atoms was set to 2. In the case of protonated aromatic nitrogen, hydrogen atoms were placed on the aromatic nitrogen, the charge was set to +1 and the number of bonded atoms was set to 3. For carboxylate anion the carbon atom was drawn bonded via any/unspecified bonds to two oxygen atom, the number of bonded atom for each oxygen atom was set to one and no charge was specified.

There are four supramolecular synthons that can be expected when a carboxylic acid and an aromatic nitrogen containing molecule occur within the same crystal structure: carboxylic acid supramolecular homosynthon I or II; carboxylic acid-pyridine supramolecular heterosynthon III; and the charge assisted form of III, i.e.

42 supramolecular heterosynthon IV (Figure 2.2). As will become clear, both statistical analysis and experimental data indicate that the formation of supramolecular heterosynthon is favored to that of supramolecular homosynthons I and II.

O O

+ O H N O H N

III IV

Figure 2.2.2. Supramolecular heterosynthons that can be formed between carboxylic acids and aromatic nitrogen: carboxylic acid-aromatic nitrogen heterosynthon III and pyridinium-carboxylate heterosynthon IV

A CSD analysis of compounds that contain at least one carboxylic acid and an

aromatic nitrogen moiety was conducted in order to determine the occurrence of the

supramolecular heterosynthon III. The percentage occurrence and hydrogen bond

distances of supramolecular synthons I-IV are presented in Table 2.1.

Table 2.1. Percentage occurrence, distance ranges, and average distance for supramolecular synthons I-VI

Number of entries Distance range [Å] Mean (σ ) [Å]

Synthon I 1683/ 7148 (23%) O-H···O 2.50-3.00 2.65(3)

Synthon II 125/7148 (1.7%) O-H···O 2.50-3.00 2.70(9) Synthon III 447/684 (65%) O-H···N 2.50-2.90 2.65(3) Synthon IV 365/368 (99%) N+-H⋅⋅⋅O- 2.40-3.00 2.67(9)

The CSD contains 684 crystal structures with both a carboxylic acid and an

aromatic nitrogen containing compound. 447 entries (ca. 65%) exhibit supramolecular

heterosynthon III as compared to 32 crystal structures (ca. 5%) that display the

43 carboxylic acid supramolecular homosynthon I or II. It should be noted that there are 11

structures that exhibit both carboxylic acid homosynthon and heterosynthon III due to the

presence of multiple carboxylic acid moieties. In the remaining structures that do not

exhibit III, the carboxylic acid functionality forms hydrogen bonds with other

competitive proton donors or acceptors such as amines, amides, water molecules,

chloride ions etc. The histogram (Figure 2.3) reveal that the COO-H··⋅Narom hydrogen

bond distances for III occur within the range of 2.50 - 2.90 Å (average 2.65(3) Å). The

same search was performed in the absence of other strong donors and/or acceptors e.g.

alcohols, 1° and 2° amides, 1° and 2° sulfonamides, imidazoles, carbonyls, nitriles, nitro-

compounds, phosphine oxides, chloride ions, bromide ions and water molecules. The

number of structures containing both carboxylic acid and aromatic nitrogen in the

absence of other competing donor and or acceptor moieties is 109. In this subset, the

percentage occurrence of III increases to 95% (104/109).

It should be noted that during the course of this work several reports have been

published regarding the use of III as a design element in crystal engineering.6,9-29 The observation of the robustness of supramolecular synthon III based upon the CSD analysis

is consistent with the experimental results of the new compounds presented herein.

44 70

Number of entries Number 20

0 2.5 2.6 2.7 2.8 2.9 3 O-H…O hydrogen bonds (Å )

20 Number of entries of Number 10

0 2.5 2.6 2.7 2.8 2.9 3 O-H…N H-bond dis tance (Å )

b) Figure 2.2.3. Histograms of contacts for: a) supramolecular homosynthon I b) O···N contacts in supramolecular heterosynthon III

2.2.2. Features of Carboxylic Acid-Aromatic Nitrogen Interaction

The difference in pKa of the carboxylic acid and the aromatic nitrogen base is often used as an indicator to determine whether neutral COO-H⋅⋅⋅Narom hydrogen bond or

proton transfer results [ΔpKa = pKa (base)- pKa (acid)]. In the pharmaceutical industry the

30 rule of thumb for salt formation is a pKa difference greater than 2 or 3 and is typically

used as a criterion for selecting counterions for salt formation. Johnson and Rumon31

45 however suggests a limit they report that a difference of pKa < 3.75 affords neutral

COOH⋅⋅⋅Narom interactions whereas ΔpK a >3.75 results in proton transfer. The formation

of the carboxylic acid-aromatic nitrogen hydrogen bond has also been rationalized in

terms of the hydrogen bond rules formulated by Etter.32

It is well known that the geometrical features of a neutral carboxylic acid group

are different from those of a carboxylate anion.33 Carboxylate anions tend to have similar

C-O bond distances whereas a neutral carboxylic acid have two distinctly different C-O

distance.34 Neutral carboxylic acids are known to have average C=O and C-O bond

distances of 1.21(2) Å and 1.31(2) Å respectively whereas deprotonated carboxylate has

average C-O bond distances of 1.25(2) Å.35 The C–N–C angle in aromatic nitrogen

moieties are also known to be sensitive to protonation,75-78 and the cationic form exhibits higher values than that of the corresponding neutral molecules. A graphical representation of the C–N–C angle distribution in both protonated and unprotonated aromatic nitrogens are presented in Figure 2.4. The average C–N–C angle encountered in

4649 neutral aromatic nitrogen is 117(2)°. In comparison, the set of 963 cationic aromatic

nitrogen exhibits higher C–N–C angles with an average value of 122(2)°. The structural features of the bond distances and bond angles are used in the analysis of the presented series of compounds.

3500

3000

2500 s

2000

1500

1000 Number of Entrie of Number

500

0 95 97 99 101 103 105 107 109 111 113 115 117 119 121 123 125 127 129 131 133 135 137 139 More . C-N-C Angle a)

600

500

s 400

300

Number ofEntrie 200

100

0 112 114 116 118 120 122 124 126 128 130 132 134 136 C-N-C Angle

Figure 2.2.4. Histograms that present the distribution of the C–N–C angle in a) neutral aromatic nitrogens and b) protonated aromatic nitrogen moieties

The pKa values of the components involved in the formation of 1-12 are presented

in Table 2.2. The difference in pKa of the base and the acid ranges from -0.93 to 3.15 and the co-crystals obtained from this study appear consistent with Johnson and Rumon’s

47 observation. There is an exception however in the case 4 which is sustained by both III and IV and the pKa difference between the initial components is 1.54.

Table 2.2. pKa values of the components of 1-12

Co-crystal pKa of acid pKa of Δ pKa component 2 [pKa(base)-pKa (acid)]

(Benzoic acid)2 ● 1,2-bis(4-pyridyl)ethane, 1 4.2 6.13 1.93

(Benzoic acid)2● trans-1,2-bis(4- 4.2 5.50 1.30 pyridyl)ethylene, 2

Benzoic acid ● 4,4’-bipyridine, 3 4.2 3.27 -0.93

4.59 6.13 1.54 (Sorbic acid)2● 1,2-bis(4-pyridyl)ethane, 4

(Naproxen)2● trans-1,2-bis(4- 4.84 5.50 0.66 pyridyl)ethylene, 5

Glutaric acid● 1,2-bis(4-pyridyl)ethane, 6 4.33 6.13 1.80

Glutaric acid● trans-1,2-bis(4- 4.33 5.50 1.17 pyridyl)ethylene, 7

Oxalic acid● tetramethylpyrazine, 8 1.38 2.88 1.50

Isophthalic acid● 1,2-bis(4-pyridyl)ethane, 9 3.53 6.13 2.60

(Trimesic acid)2●( trans-1,2-bis(4- 2.98 5.50 2.52 pyridyl)ethylene)3, 11

(Trimesic acid)2● 1,2-bis(4-pyridyl)ethane)3, 2.98 6.13 3.15 12

Melting point is still regarded as a poorly understood phenomenon however it is typically considered to arise as a consequence of the dissociation of the solid state molecular assembly.36 Melting point alternation and inversion of melting point involving co-crystals of homologous series of dicarboxylic acids and n-alkyl carboxylic acid have been reported in the literature.37-40 Melting points of the co-crystals involving 48 dicarboxylic acids n = 2-6 carbon atoms show alternation of even series having a higher melting point than odd members whereas inversion of the melting point alternation is observed within the latter series of co-crystals as compared to the pure n-alkyl carboxylic acids. Attempts to make correlation between the melting point of the obtained co-crystals and that of the initial components yielded no general conclusions. As is evident from

Table 2.3, the melting points of co-crystals 6 and 7 were higher than that of both starting materials whereas co-crystals 1, 3 and 5 had melting points lower than that of the initial components. 2, 9, 8, 11, and 12 all exhibited melting points that were between that of the co-crystal formers.

Table 2.3. Melting points of co-crystals 1-12 and corresponding starting materials

Co-crystal M. pt of co- M. pt of M. pt of crystal component 1 component 2

(benzoic acid)2● 1,2-bis(4-pyridyl)ethane, 1 80-81 121-123 107-110

(benzoic acid)2● trans-1,2-bis(4-pyridyl)ethylene, 2 128-129 121-123 150-153 benzoic acid ●4,4’-bipyridine, 3 99-102 121-123 111-114 sorbic acid● 1,2-bis(4-pyridinum)ethane sorbate, 4 110-112 134-135 107-110

(naproxen)2●trans-1,2-bis(4-pyridyl)ethylene, 5 135-137 152-154 150-153 glutaric acid●1,2-bis(4-pyridyl)ethane, 6 130-132 95-98 107-110 glutaric acid● trans-1,2-bis(4-pyridyl)ethylene, 7 180-186 95-98 150-153 oxalic acid●·tetramethylpyrazine , 8 139-142 189-190 84-86 isophthalic acid·● 1,2-bis(4-pyridyl)ethane, 9 212-222 341-343 107-110

(trimesic acid)2●( t-1,2-bis(4-pyridyl)ethylene)3, 11 228-234 378-380 150-153

(trimesic acid) ●(1,2-bis(4-pyridyl)ethane) , 12 182-186, 298- 2 3 378-380 107-110 300

49 2.2.3. Crystal Structure Description

The crystal structure of benzoic acid forms discrete adducts that are sustained by

41 2 centrosymmetric carboxylic acid dimer I, also coded as R 2 (8), graph set notation. Co-

crystallization of benzoic acid and 1,2-bis(4-pyridyl)ethane results in insertion of a

molecule of 1,2-bis(4-pyridyl)ethane between the carboxylic acid dimer. The crystal

structure of (benzoic acid)2●1,2-bis(4-pyridyl)ethane 1, reveals discrete 2:1

suppramolecular adducts sustained by symmetric COOH⋅⋅⋅Narom supramolecular

heterosynthon III. In addition to IR spectroscopic evidence, the neutral nature of III is

supported by structural data: the C-O and C=O bond distance within 1 is 1.316 Å and

1.220 Å respectively and the C-N-C bond angle within the pyridyl ring is 117.56°. The

COOH⋅⋅⋅Narom hydrogen bond distance (D: 2.5983(19) Å) occurs within the expected

range for carboxylic acid-aromatic nitrogen interactions (Table 2.1). The benzoic acid molecules are coplanar with respect to the pyridyl rings of 1,2-bis(4-pyridyl)ethane resulting in planar three component adducts. Such discrete adducts are related by

translation and are connected via weak C-H⋅⋅⋅O and hydrophobic interactions to generate

a supramolecular sheet. Such organization stack as shown in Figure 2.5a and further

stabilization of the structure is afforded by π⋅⋅⋅⋅π stacking between adjacent pyridyl rings

the centroid to centroid distance of which is 3.55Å.

(a)

(b) Figure 2.2.5. Illustrate a) discrete three component adducts of co-crystal 1, b) crystal packing in 1.

The asymmetric unit of (benzoic acid)2● trans-1,2-bis(4-pyridyl)ethylene 2,

consists of one molecule of benzoic acid and a half molecule of trans-1,2-bis(4-

pyridyl)ethylene and adopts the space group P21/c. The components form centrosymmetric three component discrete adducts sustained by supramolecular heterosynthon III (D: 2.622(2) Å]. The C-O and C=O bond distances of 1.320 Å and

1.217Å respectively and the C-N-C angle of 117.19° support the neutral nature of III.

The supramolecular trimer in 2 is planar the dihedral angle between the carboxylic acid

51 group and the pyridyl ring is 0.64°. The structure is also stabilized by π⋅⋅⋅π interaction between adjacent rings (Figure 2.6)

b) Figure 2.2.6 Illustrate a) Discrete adduct sustained by supramolecular heterosynthon III b) packing between adjacent trimeric units.

Co-crystallization of a 2:1 molar ratio of benzoic acid and 4,4’-bipyridine resulted

in the 1:1 co-crystal of benzoic acid●4,4’-bipyridine 3. The crystal structure of 3

consists of two molecules of benzoic acid and two molecules of 4,4’-bipyridine. The co-

crystal forms two component adducts sustained by supramolecular heterosynthon III [D1:

2.668(3) Å, D2: 2.655(3) Å]. The dimeric pairs align in an alternating fashion parallel to

the b axis. The dihedral angles between the planes of the pyridyl rings in the two

independent 4,4’-bipyidine molecules are 37.30° and 35.16° and in contrast to 1 and 2 the 52 hydrogen bonded adducts are not planar. The plane of the carboxylic acid is slightly

twisted with respect that of the interacting pyridyl ring of the 4, 4’-bipyidine molecule

(25.49°and 21.75°).

The neutral nature of III is supported by structural information: the C-O and C=O bond distances are 1.316 Å and 1.203Å; 1.309 Å and 1.206 Å respectively and the corresponding C-N-C angles are 116.50° and 116.70°.

Figure 2.2.7 Crystal packing of two component units in 3

The crystal structure of 4 contains one molecule of sorbic acid, a sorbate ion and a

half molecule of 1,2-bis(4-pyridyl)ethane as well as a half 1,2-bis(4-pyridinium)ethane

ion in the asymmetric unit. The crystal structure of 4 reveals discrete non-

centrosymmetric 2:1 adducts that is sustained by either supramolecular heterosynthon III

or IV. Analysis of the C-O and C=O bond distances within 4 reveal lengths of 1.322 Å

and 1.208 Å; 1.257 Å and 1.247 Å respectively and corresponding C-N-C bond angles of

115.96° and 117.29°. 53

Figure 2.2.8 Illustrates a discrete three component adduct in 4

Naproxen is a non-steroidal anti-inflammatory drug that used in the treatment of

mild to moderate pain, fever and inflammation and is marketed under the trade-name

Aleve®. Naproxen is sustained by the carboxylic acid catemer motif II.42 Co-

crystallization of naproxen with trans-1,2-bis(4-pyridyl)ethylene resulted in the formation

of co-crystal 5. The asymmetric unit of 5 contains two molecules of naproxen and one

molecule of trans-1,2-bis(4-pyridyl)ethylene. Analysis of the crystal structure reveals

discrete non-centrosymmetric three component adducts that are sustained by

supramolecular heterosynthon III (D1: 2.678(7), D2:2.876(7) Å). Such discrete adducts

stack along the b axis as shown in Figure 2.10, and π⋅⋅⋅π stacking between the trans-1,2-

bis(4-pyridyl)ethylene molecules in adjacent adducts is observed. The centroid to

centroid distance for the π stacking is 3.400Å

The C-O and C=O bond distances of the carboxylic group within the structure are

1.331 Å and 1.224 Å respectively for molecule 1; 1.311 Å and 1.213 Å for molecule 2 and the C-N-C angles within trans-1,2-bis(4-pyridyl)ethylene are 117.46 Å and 117.10Å respectively.

Figure 2.2.9 Illustrates discrete adducts of (naproxen)2 •trans-1,2-bis(4-pyridyl)ethylene, 5

Figure 2.2.10 Crystal packing in (naproxen)2 •trans-1,2-bis(4-pyridyl)ethylene, 5

The crystal structure of glutaric acid is sustained by carboxylic acid dimer I to generate infinite chains that are translationally related.43 Adjacent chains are connected

via O⋅⋅⋅O contact to generate 2D sheets as shown in Figure 2.11. Insertion of the 1,2-

bis(4-pyridyl)ethane molecules between the acid dimers of glutaric acid (GLURAC03)

occurs within 6 to generate extended chains sustained by acid-aromatic nitrogen

supramolecular heterosynthon III.

Figure 2.2.11 Crystal packing in pure glutaric acid

The crystal structure of glutaric acid● 1,2-bis(4-pyridyl)ethane 6, contains two independent molecules each of 1,2-bis(4-pyridyl)ethane and glutaric acid. 6 is sustained by supramolecular heterosynthon III. The COOH⋅⋅⋅ Narom hydrogen bonds occur within

the expected range based upon the CSD analysis. Adjacent infinite chains stack parallel

to the b axis in an ABAB fashion as shown in Fig. 2.12. There are ancillary C-H⋅⋅⋅O interactions between the carbonyl oxygen and the C-H groups adjacent to the aromatic nitrogen in the ring which further stabilize the structure and the COOH group lies generally coplanar with the pyridyl ring (C-O-N-C torsion angle is 3.37°and 6.00°).

The C-O and C=O bond distance within 6 are 1.320Å and 1.197Å; 1.314Å and

1.201Å; 1.316Å and 1.199Å; 1.326Å and 1.194 Å respectively. The C-N-C angles

within the two independent molecules of 1,2-bis(4-pyridyl)ethane are 116.97°, 117.26° and 116.75°, 117.19° thus supporting the neutral nature of the interaction.

Figure 2.2.12 Crystal structure of glutaric acid● 1,2-bis(4-pyridyl)ethane 6

The 1:1 co-crystal of glutaric acid●trans-1,2-bis(4-pyridyl)ethylene 7, is

sustained by supramolecular heterosynthon III. As is seen in 6 extended chains are

generated via symmetric COO-H⋅⋅⋅Narom hydrogen bond [2.612(3) Å, 175.3°]. Auxiliary

C-H⋅⋅⋅O hydrogen bond contributes to III and helps maintain co-planarity of the

carboxylic group and the pyridyl ring. Adjacent infinite chains stack orthogonal to -1 1 0

plane and are connected by weak C-H⋅⋅⋅O interaction to generate 2D sheets. Weak C-

H⋅⋅⋅O interactions also connect chains between adjacent layers. The neutral nature of 7 is

supported by structural information: the C-O and C=O bond distances are 1.316 Å and

1.212 Å respectively and the C-N-C angle is 118.09°.

Figure 2.2.13 Crystal structure of glutaric acid● trans-1,2-bis(4-pyridyl)ethylene, 7

Oxalic acid crystallizes in orthorhombic α and monoclinic β modifications.44 The

α polymorph forms carboxylic acid catemer II and generate supramolecular sheets whereas the metastable β modification consists of molecules of oxalic acid linked through dimer I that extend to generate infinite hydrogen bonded chains.

Oxalic acid co-crystallizes with TMP in the molar ratio 1:1 to yield crystals of oxalic acid●tetramethylpyrazine (TMP), 8. The crystal structure of 8 consists of molecules of oxalic acid and TMP residing on centers of inversion. 8 is sustained by heterosynthon III [D1: 2.7156(19) Å] to generate infinite chains. Such translationally related chains are connected via weak C-H···O interactions to generate supramolecular sheets. The C-O and C=O bond distance within 8 is 1.317 Å and 1.196Å respectively and the corresponding C-N-C bond angle is 119.75°. The dihedral angle between the plane of the oxalic acid and TMP is 53.18°. The deviation from planarity may be attributed to the presence of the methyl groups on the TMP molecule which acts as a source of steric hindrance.

Figure 2.2.14 Crystal packing of oxalic acid● tetramethylpyrazine, 8

The crystal structure of isophthalic acid●1,2-bis(4-pyridyl)ethane, 9 contains

one molecule of isophthalic acid and two half molecules of 1,2-bis(4-pyridyl)ethane in

the asymmetric unit. Co-crystal 9 is sustained by supramolecular heterosynthon III

[D1: 2.6470(18), D2: 2.5840(18)] to generate extended zig-zag chains. As is seen in

XUNGIW, 45 the co-crystal of isophthalic acid and 4,4’-bipyridine translationally related

chains align parallel to each other forming planar supramolecular 2D sheets via weak C-

H⋅⋅⋅O hydrogen bonds. The C-O and C=O bond distances are 1.306 Å and 1.214 Å; 1.318

Å and 1.210 Å respectively; and the C-N-C bond angle of 116.98° and 117.81° supports

the neutral nature of III. As is seen in 1, 2, 3, 4, 5, 6, and 7 auxillary C-H⋅⋅⋅O interactions

stabilize III and the COOH is relatively planar to the pyridyl ring, the C-O-N-C torsion

angles within 9 are 7.80° and 10.22°.

Figure 2.2.15 Crystal structure of isophthalic acid●1,2-bis(4-pyridyl)ethane, 9

As is anticipated when a molecule with one hydrogen bond donor is co-

crystallized with a molecule containing two hydrogen bond acceptor, discrete hydrogen bonded structures results as in the case of 1, 2, 3, 4 and 5. Stoichiometric 2:1 ratios of

carboxylic acid to aromatic nitrogen are observed in structures involving monoacids with

aromatic nitrogen having two acceptor sites in all cases except that of benzoic acid and

4,4’-bipyridine. However the solvent drop grinds of the 2:1 mole ratio yields a

consistently different X-ray powder diffraction pattern than is observed for the 1:1

stoichiometry suggesting the possibility of a 2:1 co-crystal as well.

Extended chains are observed in co-crystals 6, 7, 8 and 9. In all cases the ratio of

the acid and the aromatic nitrogen is 1:1 and the molecules are linked by supramolecular

heterosynthon III or IV. The geometry of the resulting chains reflects the geometry of the

linking acids in a predictable fashion. Two types of chains are seen, linear chains for co- crystals 6, 7 and 8 while zig-zag in the case of 9. In these structures weak C-H⋅⋅⋅O hydrogen bonds link parallel chains to create supramolecular sheets. 60 The multiple component crystals thus far discussed are all sustained by

supramolecular heterosynthons III or IV to generate predominantly strong hydrogen

bonded 0D and 1D motifs. However, depending on the multiplicity of the acceptors and

donors in the crystal structure, and the resulting geometry of the molecules 2D and 3D

hydrogen bonded networks may also be generated. In fact, in 1977 Wells catalogued

network structures in crystals46 in a manner that has facilitated the crystal engineering47 of a wide range of infinite 2D and 3D networks.48- 50 The topology or connectivity of a given network is represented in terms of the general symbol (n, p) where n is the number

of nodes in the smallest closed circuit in the network and p is the number of connections

to neighboring nodes that radiate from any centre or node.51 The use of either non- covalent or metal-ligand coordination bonds means that such networks are modular, i.e.,

sustained by complementary combinations of molecules or ions,52 thereby allowing the

generation of classes of compound once a prototype has been established.

Trimesic acid (benzene-1, 3, 5-tricarboxylic acid, TMA) forms hexagonal (6, 3) networks that are sustained by carboxylic acid homosynthon I.53-54 The diameter of the

hexagonal rings which consists of six molecules of TMA is 14 x 14Å. The resulting cavity is filled via interpenetration of different chicken wire frameworks. As a

consequence the α-polymorph exhibits 4-fold inclined interpenetration. The 2:3 co-

crystal of TMA and 4,4’-bipyridine, 10, represents a prototypal55 (6,3) honeycomb

network formed by two components. The co-crystal is sustained by supramolecular

heterosynthon III whereby 4,4’-bipyridine molecules act as spacers inserting between the

acid dimer I thereby expanding the 14 × 14 Å TMA cavity to ca. 35 × 26Å. The

hexagonal cavity is filled by 3-fold parallel interpenetration of independent networks. 61 Co-crystallization of TMA and trans-1,2-bis(4-pyridyl)ethylene results in the formation of the (TMA)2● (trans-1,2-bis(4-pyridyl)ethylene)3, 11. There are two

molecules of TMA and three molecules of trans-1,2-bis(4-pyridyl)ethylene in the

asymmetric unit. Co-crystal 11 exhibits hexagonal (6, 3) networks that are sustained by

supramolecular heterosynthon III. An expanded cavity size of 41 x 35 Å dimension is

observed without changing the network topology of pure TMA. As is seen in the

prototypal co-crystal 3-fold parallel interpenetration is observed.

a) b) Figure 2.16. Super honeycomb (6, 3) network (a) and Space filling view of triply parallel interpenetrated (b) nets of 11

The X-ray crystal structure of (TMA)2● (1,2-bis(4-pyridyl)ethane)3, 12a

confirms the expected 2:3 stoichiometry and the presence of supramolecular

heterosynthon, III. However, 12a does not exist as a (6, 3) network. Rather, 12a forms a

supramolecular isomer48 that is better known in the context of coordination polymers, a

(10, 3)-a network.46, 49 The scale of the molecular components means that the dimensions

of the channels in the network are ca. 53 × 30 Å (Figures 2.17). A distinguishing feature

of (10, 3)-a networks is the presence of 4-fold helices, all of the same handedness, that

62 align parallel to the three cubic axes. 12a contains a set of three (10, 3)-a nets of the

same handedness that triply interpenetrate as shown in Figure 2.18a. This set in turn

interpenetrates with two other sets of the same handedness, thereby generating 9-fold

interpenetration along the b-axis (Figure 2.18b). Further interpenetration between

oppositely handed sets of nets affords 18-fold interpenetration (Figure 2.18c). To our

knowledge this is the highest level of interpenetration yet observed in a net, the previous

record being 11-fold.56-57

(a) (b)

Figure 2.2.16 Space filling views of a single (10,3)-a network of 12a: the ca. 53 × 30 Å channel viewed down the c-axis; a view orthogonal to the c-axis.

(a) (b)

(c) Figure 2.2.17 Schematic illustrations of the interpenetration in 12a: (a) A set of triply interpenetrated (10,3)-a nets; (b) 9-fold interpenetration, each color represents a set of triply interpenetrated (10,3)-a nets; (c) The six sets of triply interpenetrated nets that afford overall 18-fold interpenetration

The X-ray crystal structure of (TMA)2● (1,2-bis(4-pyridyl)ethane)3, 12b reveals that it exhibits the expected (6, 3) network with linear 1,2-bis(4-pyridyl)ethane molecules expanding the 14 × 14 Å TMA cavity to ca. 39 × 27 Å. The prototypal structure of 10 64 exhibited a similar expansion of ca. 35 × 26 Å.55 Three (6, 3) networks engage in parallel

interpenetration as illustrated in Figure 3.19. The void left over after catenation is filled by interdigitation of TMA and 1,2-bis(4-pyridyl)ethane molecules from adjacent layers.

Nangia and co-workers have observed similar behavior in another trigonal scaffold,

cyclohexane-1,3cis,5cis-tricarboxylic acid (CTA) and have generated a related series of super honeycomb networks.58-59 The network topology and mode of interpenetration in

2:3 co-crystals of CTA•1,2-bis(4-pyridyl)ethane59 is closely related to that observed in

10, 11 and 12b. It should also be noted that TMA•1,2-bis(4-pyridyl)ethane salt structures

have been reported 60-62 but they do not exhibit interpenetration. That 12a and 12b are

indeed molecular co-crystals is supported by location of hydrogen atoms in Fourier maps,

examination of C−O and C=O bond distances, C−N−C angles and IR spectroscopy.

(a) (b) Figure 2.19 Super honeycomb (6,3) network (a) and Space filling view of triply parallel interpenetrated (b) nets of 12b

65 The existence of (10,3) networks and supramolecular isomerism in coordination

polymers is well documented but to our knowledge there exist only five neutral hydrogen

bonded (10,3)-a nets that are built from organic molecules and they are not yet known to

be polymorphic.63-64 Robson and co-workers recently reported a series of non-

65 interpenetrated (10,3)-a networks in [C(NH2)3][N(CH3)4][XO4](X= S, Cr, Mo).

However to the best of our knowledge, 12a represents the first observation of a hydrogen

bonded (10,3)-a network in a co-crystal. Polymorphism in co-crystals is also a relatively

rare phenomenon, especially when compared to single component molecular

crystals.65Indeed, only three previous examples of concomitant polymorphism in co- crystals have been reported and are a consequence of conformational effects.66-68

A number of methodologies were employed in the synthesis of the presented series of co-crystals. Co-crystallization experiments were attempted via slow evaporation, melting, grinding and solvent drop grinding techniques. The latter synthetic approaches can be advantageous from a green chemistry perspective. Additionally, the solvent-drop grinding approach has been shown to be useful in addressing the issue of stoichiometry and polymorph control in co-crystals.7 Solvent-drop grinding results suggest that it is

generally possible to find experimental conditions, under which a specific co-crystal form

exists. With regards to the stoichiometry and the crystal form 1, 2, 3, 4, 5, 6, 7, 8, 9 and

11 were reproduced using the aforementioned techniques. (TMA)2•(1,2-bis(4-

pyridyl)ethane)3 was found to exist in two polymorphic modifications. While solution

crystallization afforded concomitant polymorphs form I (12a) and form II (12b), both

grinding and solvent drop grinding resulted in a mixture of starting materials.

66 A screen for crystal forms of 1-9 and 11 was conducted via solvent drop grinding of co-crystal formers involving seven solvents of different polarity. As determined by infrared spectroscopy and X-ray powder diffraction, only one form was isolated for 1-9 whereas 11 was only obtained from solvent drop using dimethyl sulfoxide. The solvent

drop grinding experiments tend to mirror the co-crystals that were obtained from

solution. A screen for crystal forms of 12 was conducted using seventeen solvents.

Solvent drop grinding involving isopropanol, chloroform, dichloromethane, cyclohexane,

heptane, ethyl acetate, tetrahydrofuran, acetonitrile, isopropyl acetate, methanol, heptane,

DMA and DMSO resulted in a mixture of starting materials whereas solvent drop grinds

involving toluene, acetone and yielded a new phase that was different from 12a and or

12b. The utilization of solid state co-crystallization of 1-9 and 11 indicates that such

methods are viable means for supramolecular synthesis of co-crystals.

2.3. Conclusions

Hydrogen bonded supramolecular synthons in a series of co-crystals containing

carboxylic acids and aromatic nitrogen have been studied using X-ray diffraction. The

hydrogen bonding in these co-crystals support the statistical analysis that indicate that the

acid-pyridine supramolecular heterosynthon III is favored over the formation of the

carboxylic acid supramolecular homosynthons I or II. Consequently the relative ranking

of these supramolecular synthons can be presented as: III>I>II.

Co-crystal 12 exhibits concomitant polymorphism and one form exhibits the

highest level of interpenetration yet observed in an organic or metal-organic network.

The observation of polymorphism in a co-crystals is of topical interest given the growing

67 relevance of pharmaceutical co-crystals.6, 9, 69-71 The existence of a (10, 3)-a network

with such large dimensions and the inherent modularity of co-crystals illustrates how co- crystals of TMA might be worthy of further investigation in the context of open framework networks especially as a recent study suggests that interpenetrated metal- organic networks are of interest in the context of hydrogen gas storage.70

The majority of API’s in the pharmaceutical industry tend to have low water solubility. Particle size reduction by milling or grinding is typically performed as a means of improving the dissolution rate and there exists a correlation between particle size reduction and bulk properties such as flowability, bulk density, mixing ability etc. That the co-crystals within the study and co-crystals in general may be synthesized via grinding and solvent drop grinding has significant implication with respect to processing of these novel materials and green chemistry.

68 2.4. Experimental Section

All reagents were purchased from Aldrich and used without further purification.

Single crystals of 1-12 were obtained via slow evaporation of stoichiometric amounts of starting materials in appropriate solvents and were isolated from solution before complete evaporation of the solvents.

2.4.1. Co-crystallization via grinding:

Stoichiometric amounts of the starting materials were ground with a mortar and pestle for ca.4 minutes.

2.4.2. Co-crystallization via solvent-drop grinding:

Stoichiometric amounts of the starting materials were ground with a mortar and pestle for ca. 4 minutes with the addition of 10 μL of solvent per 50 mg of co-crystal formers.

2.4.3. Co-crystallization via melting: Stoichiometric amounts of the starting materials were heated until melt and the mixture was left to crystallize at ambient conditions.

2.4.4. Co-crystallization via solution evaporation:

(Benzoic acid)2 ● 1,2-bis(4-pyridyl)ethane, 1: 1,2-bis(4-pyridyl)ethane (0.037g, 0.20 mmol) and benzoic acid (0.049g, 0.40mmol) was dissolved in a 1:1 ethanol/methanol solvent mixture (2 mL) . After three days colorless crystals of 1 were obtained, m. pt: 110-112°.

(Benzoic acid)2● trans-1,2-bis(4-pyridyl)ethylene, 2: To trans-1,2-bis(4- pyridyl)ethylene (0.039g, 0.21mmol) was added benzoic acid (0.052g, 0.42 mmol) and

69 2 mL of a 1:1 ethanol/methanol solvent mixture. Colorless rods of 2 were observed

within five days, m. pt: 80-81°.

Benzoic acid●4,4’-bipyridine, 3: Benzoic acid (0.049g, 0.40mmol) and 4,4’-bipyridine

(0.032g, 0.20mmol) was dissolved in of acetonitrile (2 mL). The solution was allowed to

slowly evaporate at room temperature to yield colorless blocks of 3, m. pt: 128-129°

Sorbic acid● 1,2-bis(4-pyridinium)ethane sorbate, 4: Sorbic acid (0.022g, 0.20mmol)

and 1,2-bis(4-pyridyl)ethane (0.018g, 0.10mmol) was dissolved in 1:1 ethanol/methanol

solution (2 mL). The solution was allowed to slowly evaporate at room temperature to yield colorless crystals of 4 after three days, m. pt: 99-103°.

(Naproxen)2●trans-1,2-bis(4-pyridyl)ethylene, 5: Naproxen (0.080g, 0.34mmol) and

trans-1,2-bis(4-pyridyl)ethylene (0.032g, 0.17mmol) was dissolved in 1:1

ethanol/methanol solution (2 mL). The solution was allowed to slowly evaporate at

ambient temperature to yield crystals of 5, m. pt: 135-137°.

Glutaric acid● 1,2-bis(4-pyridyl)ethane, 6: Slow evaporation of a 1:1 ethanol/methanol

solution (2mL) containing glutaric acid (0.027g, 0.20mmol) and 1,2-bis(4-pyridyl)ethane

(0.034g, 0.20mmol) yielded colorless crystals of 6, after two days, m. pt: 130-132°.

Glutaric acid●trans-1,2-bis(4-pyridyl)ethylene, 7: Glutaric acid (0.027g, 0.20mmol) and trans-1,2-bis(4-pyridyl)ethylene (0.036g, 0.20mmol) was dissolved in a 1:1 ethanol/methanol solution (2mL). After two days, colorless crystals of 7 were obtained upon slow evaporation, m. pt: 180-186°.

Oxalic acid● tetramethylpyrazine, 8: Tetramethylpyrazine (0.015g, 0.11mmol) and

oxalic acid (0.0095g, 0.11mmol) was dissolved in ethylacetate (2 mL) on heating. Upon

slow evaporation colorless rods of 8 was obtained, m. pt: 139-142°. 70 Isophthalic acid● 1,2-bis(4-pyridyl)ethane, 9: To 1,2-bis(4-pyridyl)ethane (0.048g,

0.26mmol) was added isophthalic acid (0.044g, 0.27mmol) and the solid mixture

dissolved in DMSO (0.5mL). Colorless crystals of 9 were observed within four days, m.

pt: 212-222°.

(Trimesic acid)2●( trans-1,2-bis(4-pyridyl)ethylene)3, 11: Trimesic acid (0.077mg,

0.37mmol) and trans-1,2-bis(4-pyridyl)ethylene (0.100g, 0.55 mmol) was dissolved in

DMSO (1 mL). After 3 days, small yellow blocks were obtained to yield co-crystal 11, m. pt: 228-234°.

(Trimesic acid)2● 1,2-bis(4-pyridyl)ethane)3, 12: Trimesic acid (0.030g, 0.14mmol)

and trans-1,2-bis(4-pyridyl)ethylene (0.039g, 0.21mmol) was dissolved in DMSO (1mL)

. The solution was left to slow evaporate at room temperature. Colorless crystals of 12

were obtained within 3 days, m. pt: 182-186°, 298-300°.

Polymorphism Screen

1-12 were subjected to a preliminary polymorph screen using solvent drop grinding (as

described above) with seven solvents that exhibit a wide range of polarity: cyclohexane,

toluene, chloroform, ethyl acetate, methanol, dimethyl sulfoxide (DMSO) and water. A

summary of the results obtained from dry grinding, solvent drop grinding and melts are

presented in Table 2.4. In addition to the co-crystal, trace amounts of starting material

was also observed in the case of 1, 2, 3, 8, 9 and 11

71 Table 2.4 Results obtained from solution crystallization, grinding, solvent drop grinding and melting experiments

Solution Grinding Solvent-drop Melt grinding

1 1 1 1 1

2 2 2 2 2

3 3 3 3 3

4 4 4 4 4

5 5 5 5 5

6 6 6 6 6

7 7 7 7 7

8 8 8 8 8

9 9 9 9 n/a

starting 11 11 11* n/a material

12 12 starting New form + n/a material starting material

All compounds were analyzed by infrared spectroscopy using a Nicolet Avatar

320 FTIR instrument. The purity of bulk samples was confirmed by X-ray powder

diffraction analysis conducted on a Rigaku Miniflex Diffractometer using Cu Kα (λ=

1.540562), 30kV, 15mA. The data were collected over an angular range of 3° to 40° 2θ in continuous scan mode using a step size of 0.02° 2θ and a scan speed of 2.0º/min.

The X-ray powder diffraction analysis of the powders obtained in the polymorphism screens for 1, 2, 3, 4, 6, 7, 8, 9, 11, and 12 were collected on Bruker AXS

D8 discover X-ray diffractometer equipped with GADDSTM (General Area Diffraction

Detection System), a Bruker AXS HI-STAR area detector at a distance of 15.05 cm as

72 per system calibration, a copper source, automated x-y-z stage, and 0.5 mm collimator.

Data were collected over a 2θ range of 2.0-37.0 at a step size of 0.02° 2θ.

The melting points were determined on a Mel-temp® apparatus and are presented

in Table 2.1. Differential Scanning Calorimetry was performed using a TA instrument

model 2140, 10° step/min.

2.4.5. Crystal structure determination

Crystals 1-12 were examined under a microscope and suitable single crystals were

selected for X-ray analysis. Data were collected on a Bruker–AXS SMART APEX CCD

diffractometer with monochromatized Mo Kα radiation (λ = 0.71073 Å) connected to a

KRYO-FLEX low temperature device. Data for 1, 4-5, 8-9, 11-12 were collected at 100

K whereas data for 2-3, 6-7 were collected at 298 K. Lattice parameters were determined

from least square analysis, and reflection data were integrated using the program

SAINT+ Version 6.22. Lorentz and polarization corrections were applied for diffracted

reflections. In addition, the data was corrected for absorption using SADABS. Structures

were solved by direct methods and refined by full matrix least squares based on F2 using

SHELXTL74 software Version 6.10. All non-hydrogen atoms were refined with

anisotropic displacement parameters. All H-atoms bonded to carbon atoms, except

methyl groups, were placed geometrically and refined with an isotropic displacement

parameter fixed at 1.2 times Uq for the atoms to which they were attached. H-atoms of

methyl groups as well as N or O bonded protons were located from Fourier difference

map and refined isotropically based upon the corresponding N or O-atom

73 (U(H)=1.2Uq(N, O)). Crystallographic data for 1-12 are presented in tables 2.4 and 2.5 and selected hydrogen bond distances are presented in table 2.6.

Table 2.4. Crystallographic data and Parameters for 1-12

1 2 3 4 5 6

Formula C26H24N2O4 C26H22N2O4 C17H14N2O2 C24H28N2O4 C40H38N2O6 C17H18N2O4

Mol .wt. 428.47 426.46 278.30 408.48 642.72 314.33

Crystal system Triclinic Monoclinic Triclinic Monoclinic Triclinic Monoclinic

Space group P-1 P2(1)/c P-1 C2/c P1 C2/c

a/Å 6.4357(17) 8.8678(13) 7.608(2) 25.377(5) 5.7645(16) 15.562(6)

b/Å 6.8960(18) 4.9009(7) 11.454(3) 12.669(3) 7.607(2) 10.281(4)

c/Å 12.412(3) 24.411(4) 16.423(5) 14.754(3) 19.109(5) 9.436(4)

αº 79.037(5) 90 100.293(5) 90 84.851(5) 90

βº 80.952(5) 99.524(3) 95.987(6) 98.68(3) 83.797(5) 92.357(7)

γº 80.144(5) 90 90.521(5) 90 89.241(5) 90

V /Å3 528.4(2) 1046.3(3) 1399.8(7) 4689.1(4) 829.7(4) 1508.4(10)

-3 Dc/g cm 1.347 1.354 1.321 1.157 1.286 1.384

Z 1 2 4 8 1 4

2θ range 3.38-52.74 3.38-49.42 2.54-49.42 4.40-49.58 2.16-50.20 5.24-52.74

Nref./Npara. 2102/145 1760/145 4679/ 379 3994/324 2928/433 1542/105

T/K 100(2) 100(2) 298(2) 298(2) 100(2) 100(2)

R1 [I>2sigma(I)] 0.0516 0.0508 0.0638 0.0681 0.0611 0.0820

wR2 0.1385 0.1355 0.1649 0.1957 0.1474 0.2258

GOF 1.083 1.097 1.087 0.995 1.050 1.134

Abs coef. 0.091 0.092 0.088 0.079 0.087 0.100

Table 2.5. Crystallographic data and Parameters for 1-12

7 8 9 11 12a 12b

Formula C17H20N2O4 C10H14N2O4 C20H18N2O4 C27H21N3O6 C54H48N6O12 C27H24N3O6

Mol .wt. 316.35 226.23 350.36 483.47 972.98 486.49

Crystal system Monoclinic Triclinic Triclinic Monoclinic Orthorhombic Monoclinic

Space group P2(1)/c P-1 P-1 P2(1)/n Pbca P2(1)/n a/Å 12.295(3) 3.8081(9) 6.9526(17) 10.214(3) 19.270(3) 10.344(2) b/Å 11.166(2) 8.3558(19) 7.4920(18) 12.391(3) 19.906(3) 12.313(2) c/Å 24.421(5) 8.606(2) 17.118(4) 18.630(5) 25.249(3) 18.914(4)

αº 90 81.950(4) 100.783(4) 90 90 90

βº 97.102(4) 80.337(4) 90.162(4) 98.129(6) 90 94.309(4)

γº 90 85.847(4) 101.822(4) 90 90 90

V /Å3 3326.8(12) 266.97(11) 856.5(4) 2334.2(10) 9685(2) 2402.3(8)

Dc/g cm-3 1.263 1.407 1.358 1.376 1.335 1.345

Z 8 1 2 4 8 4

2θ range 3.34-52.74 4.84-52.74 2.42-52.74 3.96-52.74 3.22-49.42 3.96-49.42

Nref./Npara. 6760/415 1069/73 3417/235 4761/334 8249/650 4096/ 325

T/K 298(2) 100(2) 298(2) 100(2) 100(2) 100(2)

R1 0.0844 0.0654 0.0514 0.0734 0.0557 0.0626 [I>2sigma(I)] wR2 0.2321 0.1792 0.1405 0.1720 0.1262 0.1242

GOF 1.058 1.061 1.050 1.001 1.062 0.906

Abs coef. 0.091 0.110 0.096 0.099 0.096 0.096

75 Table 2.6. Selected Hydrogen Bond Distances and Parameters for 1-12

Hydrogen Bond d (H···A) /Å D (D···A)/Å θ /º

1 O-H⋅⋅⋅⋅N 1.68 2.5983(19) 175.0 2 O-H⋅⋅⋅⋅N 1.65 2.622(2) 170.9 3 O-H⋅⋅⋅⋅N 1.73 2.668(3) 171.2 O-H⋅⋅⋅⋅N 1.69 2.655(3) 171.3 5 O-H⋅⋅⋅⋅N 1.66 2.678(7) 172.9 O-H⋅⋅⋅⋅N 1.59 2.687(7) 158.1 O-H⋅⋅⋅⋅N 1.79 2.647(3) 174.9 6 O-H⋅⋅⋅⋅N 1.83 2.657(3) 156.2 O-H⋅⋅⋅⋅N 1.81 2.632(3) 174.2 O-H⋅⋅⋅⋅N 1.74 2.657(3) 155.4 7 O-H⋅⋅⋅⋅N 1.74 2.612(3) 175.3 8 O-H⋅⋅⋅⋅N 1.81 2.7156(19) 174.2 9 O-H⋅⋅⋅⋅N 1.74 2.6470(18) 173.7 O-H⋅⋅⋅⋅N 1.61 2.5840(18) 171.2 O-H⋅⋅⋅⋅N 1.63 2.623(4) 160.9 11 O-H⋅⋅⋅⋅N 1.57 2.597(4) 170.5 O-H⋅⋅⋅⋅N 1.66 2.622(4) 168.2 O-H⋅⋅⋅⋅N 1.64 2.601(3) 174.3 O-H⋅⋅⋅⋅N 1.67 2.622(3) 161.6

O-H⋅⋅⋅⋅N 1.59 2.621(3) 178.1 12a O-H⋅⋅⋅⋅N 1.33 2.553(3) 175.5 O-H⋅⋅⋅⋅N 1.64 2.625(3) 167.7

O-H⋅⋅⋅⋅N 1.62 2.607(3) 173.5 O-H⋅⋅⋅⋅N 1.50 2.596(4) 163.7 12b O-H⋅⋅⋅⋅N 1.56 2.605(4) 175.2 O-H⋅⋅⋅⋅N 1.51 2.614(4) 169.9

76 2.5. References Cited

1. Leiserowitz, L. Acta Crystallogr., 1976, B32, 775.

2. Allen, F. H.; Kennard, O. Chem. Des. Automation News, 1993, 8, 31.

3. Allen, F. H.; Kennard, O.; Taylor, R. Acc. Chem. Res., 1983, 16, 146.

4. Allen, F. H. Acta Crystallogr., 2002, B58, 380.

5. Allen, F. H, Taylor, R. Chem. Soc. Rev., 2004, 33, 463.

6. Walsh, R. B. D.; Bradner, M. W.; Fleishman, S.; Morales, L. A.; Moulton, B.;

Rodriquez-Hernedo, N.; Zaworotko, M. J. Chem Commun., 2003, 186.

7. Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 20, 2372.

8. Bernstein, J. Polymorphism in Molecular Crystals; Claredon Press: Oxford, United

Kingdom, 2002.

9. Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.;

Guzman, H. R.; Almarsson, O. J. Amer. Chem. Soc., 2003, 125, 8456.

10. Wheatley, P. S.; Lough, A. J.; Ferguson, G.; Glidewell, C. Acta Crystallogr., 1999,

C55, 1489.

11. Wheatley, P. S.; Lough, A. J.; Ferguson, G.; Glidewell, C. Acta Crystallogr., 1999,

C55, 1486.

12. Nguyen, T. L.; Fowler, F. W.; Lauher, J. W. J. Amer. Chem. Soc. 2001, 123,

11057.

13. Kane, J. J.; Liao, R..; Lauher, J. W.; Fowler, F. W. J. Amer. Chem. Soc. 1995, 117,

12003.

14. Chatterjee, S.; Pedireddi, V. R.; Rao, C. N. R. Tet. Lett., 1998, 39, 2843.

77 15. Pedireddi, V. R.; Chatterjee, S.; Ranganathan, A.; Rao, C. N. R Tetrahedron, 1998,

54, 9457.

16. Pedireddi, V. R. Cryst. Growth Des. 2001, 1, 383.

17. Arora, K. K.; Pedireddi, V. R. J. Org. Chem., 2003, 68, 9177.

18. Garcia-Tellado, F.; Geib, S. J.; Goswami, S.; Hamilton, A. D. J. Amer. Chem. Soc.

1991, 113, 9265.

19. Lynch, D. E.; Smith, G.; Byriel, K. A.; Kennard, C. H. L Acta Crystallogr., 1994,

C50, 1291.

20. Kumar, V. S.; Kuduva, S. S.; Desiraju, G. R. Acta Crystallogr., 2002, E58, 865.

21. Bond, A. D. Chem. Commun., 2003, 250.

22. Shan, N.; Bond, A. D.; Jones, W. Cryst. Eng. 2002, 5, 9.

23. Shan, N.; Bond, A. D.; Jones, W. Tet. Lett., 2002, 43, 3101-3104,

24. Olenik, B.; Smolka, T.; Boese, R.; Sustmann, R. Cryst. Growth Des. 2003., 3, 183.

25. Etter, M. C.; Adsmond, D. A.; Britton, D. Acta Crystallogr., 1990, C46, 933-4,.

26. Batchelor, E.; Klinowski, J.; Jones, W. J. Mater. Chem., 2000, 10, 839.

27. Shan, N.; Batchelor, E.; Jones, W. Tet. Lett., 2002, 43, 8721.

28. Smolka, T.; Schaller, T.; Sustmann, R.; Blaser, D.; Boese, R. J. Prakt. Chem.,

2000, 342, 465.

29. Zhang, J.; Wu, L.; Fan, Y. J. Mol. Struct., 2003, 660, 119.

30. Stahl, P.H.; Wermuth, C. G. ed. Handbook of pharmaceutical salts: properties,

selection, and use; International Union of Pure and Applied Chemistry, VHCA;

Wiley-VCH: Weinheim, New York, 2002.

31. Johnson, S. L.; Rumon, K. A. J. Phys. Chem., 1965, 69, 74.

78 32. Etter, M. C. Acc. Chem. Res. 1990, 23, 120.

33. Aakeroy, C. B.; Hussain, I.; Desper, J. Cryst. Growth Des. 2006, 6, 474-480.

34. Borthwick, P. W. Acta Crystallogr. 1980, B36, 628

35. Bis, J. A.; Zaworotko, M. J. Crystal Growth Des., 2005, 5, 1169-1179.

36. Cotterill, R. M. J. J. Cryst. Growth, 1980, 48, 582.

37. Vishweshwar, P.; Nangia, A.; Lynch, V. M. Crystal Growth Des. 2003, 3, 783.

38. Bond, A. D. New J. Chem., 2004, 28, 104.

39. Bond, A. D. CrystEngComm., 2006, 8, 333.

40. Smith, J. C.; Shenton, T. Tetrahedron, Supplement, 1966, 7, 45.

41. Sim, G. A.; Robertson, J. M.; Goodwin, T. H.; Acta Crystallogr., 1955, 8, 157.

42. Ravikumar, K.; Rajan, S .S.; Pattabhi, V.; Gabe, E. J. Acta Crystallogr., 1985,

C41, 280.

43. CSD Refcodes: GLURAC, GLURAC02, GLURAC03, GLURAC04.

44. Thalladi, V. R.; Nüsse, M.; Boese, R. J. Am. Chem. Soc. 2000, 122, 9227-923.

45. CSD Refcode: XUNGIW

46. Wells, A. F. Three-dimensional Nets and Polyhedra, Wiley Interscience, New

York, 1977.

47. Desiraju, G. R. Crystal Engineering. The Design of Organic Solids; Elsevier:

Amsterdam, 1989.

48. Moulton, B.; Zaworotko, M. J. Chem. Rev. 2001, 101, 1629.

49. Batten, S. R.; Robson, R. Angew. Chem. Int. Ed. 1998, 37, 1460.

50. Carluci, L.; Ciani, G.; Proserpio, D. M. Coord. Chem. Rev. 2003, 246, 247.

51. Janiak, C. Dalton Transactions, 2003, 2781.

79 52. Zaworotko, M. J. Chem. Soc. Rev. 1994, 23, 283.

53. Herbstein, F. H. in Comprehensive Supramolecular Chemistry; MacNicol, D. D.,

Toda, F., Bishop, R., Eds.; Pergamon: Oxford, 1996; Vol. 6, pp 61−83.

54. Duchamp, D. J.; Marsh, R. E. Acta Crystallogr. 1969, B25, 5.

55. Sharma, C. V. K.; Zaworotko, M. J. Chem. Commun. 1996, 2655.

56. Reddy, D. S.; Dewa, T.; Endo, K.; Aoyama, Y. J. Am. Chem. Soc. 2000, 112, 4436.

57. A compendium of interpenetration can be found at Dr. S. R. Batten’s web page:

http://web.chem.monash.edu.au/Department/Staff/Batten/mainpage.htm

58. Bhogala, B.R.; Vishweshwar, P.; Nangia, A. Cryst. Growth Des. 2002, 2, 325.

59. Bhogala, B. R.; Nangia, A. Cryst. Growth Des. 2003, 3,

60. Paz, F. A. A.; Bond, A. D.; Khimyak, Y. Z.; Klinowski, J. New J. Chem. 2002, 26,

381.

61. Paz, F. A. A.; Klinowski, J. CrystEngComm 2003, 5, 238.

62. Boldog, I.; Rusanov, E. B.; Sieler, J.; Blaurock, S.; Domasevitch, K. V. Chem.

Commun. 2003, 740.

63. Denner, L.; Luger, P.; Buschmann, J. Acta Crystllogr. 1988, C44, 1979.

64. Abrahams, S. C.; Collin, R. L.; Lipscomb, W. N. Acta Crystallogr. 1951, 4, 15.

65. Abrahams, B. F.; Haywood, M. G.; Hudson, T. A.; Robson, R. Angew. Chem. Int.

Ed. 2004, 43, 6153.

66. The CSD contains only 24 polymorphic co-crystals that are sustained by strong

hydrogen bonds and data has been deposited on only 9 of these compounds. 1623

80 polymorphic single component crystals exist. Vishweshwar, P.; McMahon, J.A.;

Zaworotko, M.J. Crystal Engineering of Pharmaceutical Co-crystals. In Frontiers in

Crystal Engineering, Eds. Tiekink, E.; Vittal, J. J. 2005, Wiley, Chichester, UK.

67. Bowes, K. R.; Ferguson, G.; Lough, A. J.; Glidewell, C. Acta Crystllogr. 2003,

B59, 277.

68. Trask, A.V.; Motherwell, W.D.S.; Jones, W. 2004, 890.

69. McMahon J.A.; Bis, J.A.; Vishweshwar, P.; Shattock, T.R; McLaughlin, O.L.;

Zaworotko, M. J. Zeit. Für Krist. 2005, 220, 340.

70. Almarsson, O; Bourghol Hickey, M.; Peterson, M.; Zaworotko, M. J.; Moulton, B.;

Rodriguez-Hornedo, N. PCT Int. Appl. WO 2004078161, 2004.

71. Fleischman, S. G.; Kuduva, Srinivasan S.; McMahon, J. A.; Moulton, B.; Walsh,

Rosa D. B.; Rodriguez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des. 3, 909-

919, 2003.

72. Kesanli, B.; Cui, Y.; Smith, M. R.; Bittner, E. W.; Bockrath, B. C.; Lin, W. Angew.

Chem. Int. Ed. 2005, 44, 72.Boenigk, D.; Mootz, D. J. Am. Chem. Soc. 1988, 110,

2135.

73. SADABS [Area-Detector Absorption Correction]. Siemens Industrial Automation,

Inc.: Madison, WI, 1996.

74. Sheldrick, G. M. SHELXTL University of Gottingen: Germany, 1997.

75. Boenigk, D.; Mootz, D. J. Am. Chem. Soc. 1988, 110, 2135. 81 76. Cowan, J. A.; Howard, J. A. K.; McIntyre, G. J.; Lo, S. M. F.; Williams, I. D. Acta

Crystallogr. 2003, B59, 794.

77. Mootz, D.; Wussow, H. G. J. Chem. Phys. 1981, 75, 1517.

78. Mootz, D.; Hocken, J. Z. Naturforschung B J. Chem. Sci. 1989, 44, 1239.

3. The Reliability of the Alcohol−Aromatic Nitrogen Supramolecular

Heterosynthon

3.1. Introduction

Crystal Engineering is the rational design of functional solids.1 Consequently one

of the main goals is to control the way in which individual molecules self assemble in the

solid state, allowing us to affect solid state reactivity and to design new functional

materials. A pre-requisite in the design process is the identification of reliable, robust

supramolecular synthons since it affords a certain level of predictability with respect to

anticipated pattern formation in the crystal structure and allows for the judicious selection

of co-crystal formers. In a continuing effort to assess how functional groups self-

associate i.e form supramolecular homosynthons2 versus their interactions with different

complementary groups to form supramolecular heterosynthons, the system of alcohols

and aromatic nitrogens were chosen. The study involved assessing the reliability of the

alcohol homosynthon as compared to the alcohol-aromatic nitrogen heterosynthon.

Alcohols represent one of the most prevalent functional groups found in nature

and in pharmaceuticals. They are self complementary since they are capable of acting as

both hydrogen bond donor and hydrogen bond acceptor. Self-association of alcohols

mediated by hydrogen bonds has been studied3 and they are known to form chains, rings

(pentemers, hexamers etc) or helices through O-H⋅⋅⋅O hydrogen bonds. Of the 24,995 83 entries that contain an alcohol group in the Cambridge Structural Database (CSD)4-7 6183

(ca. 25%) self associate via hydrogen bonds to form supramolecular homosynthon V.

Alcohols are also capable of forming supramolecular heterosynthons with a number of different complementary functional groups such as aromatic nitrogen, carbonyls, phosphonyls, sulfonyls, etc.

The utilization of the alcohol-aromatic nitrogen supramolecular heterosynthon VI

in crystal engineering is certainly not without precedence. In fact several examples of co-

crystals8-24 based upon supramolecular heterosynthon VI exist in the CSD. VI has been

utilized to build crystals with intricate supramolecular architectures25-31, to synthesize

host-guest complexes, 31-38 for non-linear optics39 and as supramolecular template to

direct topochemical reactions.40-41

In the present study, hydrogen bonded co-crystals formed between aromatic nitrogen and alcohols are investigated in the context of the reliability of supramolecular synthons formed.

84 OH

OH OH HO OH HO OH

OH OH 1-naphthol hydroquinone resorcinol 2,7-dihydroxynaphthalene 4,4'-biphenol

H3C N CH3 N N N N H3C N CH3

1,2-bis(4-pyridyl)ethane trans-1,2-bis(4-pyridyl)ethylene tetramethylpyrazine (TMP)

Figure 3.1 Molecular structures of components used in co-crystallization of 13-20.

3.2. Results and Discussion

3.2.1. Cambridge Structural Database Analysis

A statistical analysis of the CSD revealed the percentage of occurrence and the

parameters of supramolecular synthons V and VI. For each supramolecular synthon

considered, initial contact distances well beyond the sum of the Van der Waals radii of

the acceptor and the donor atoms were applied. Contact limits for each interaction was

subsequently determined from histogram. Crystal structures at the end of the bell curve

(visual limits) were examined more closely in Mercury. The parameters used to define the searches were 3D-coordinates present, only organics and R < 7.5%.

85 H OH O OH N C C C

V VI

Table 3.1 Geometric features of supramolecular homosynthon V and supramolecular heterosynthon VI.

Supramolecular Percentage Interaction Distance Range Mean (Å) Synthon (Å)

V 6183/24994 O-H⋅⋅⋅⋅O 2.50-3.07 2.78(8) (24.7%)

VI 682/1453 (46.9%) O-H⋅⋅⋅⋅Narom 2.50-3.00 2.77(8)

There are 1453 entries that contain both an alcohol and an aromatic nitrogen

containing molecule in the CSD. Of this number, 682 (47%) entries exhibit

supramolecular heterosynthon VI as compared to 274 (19%) crystal structures that

exhibit the alcohol homosynthon V. 517 of the 682 structures exhibiting VI were found

to occur exclusive of the alcohol homosynthon. A further analysis revealed 208 structures

in which an aromatic nitrogen and an alcohol are present in the absence of any other hydrogen bonding moieties. 203 of these structures (97%) exhibit heterosynthon VI as compared to 52 structures (26%) that exhibit V, suggesting that VI is favored over V

even in the presence of competing functional groups.

The alcohol-aromatic nitrogen heterosynthon was found to occur within the range

2.50-3.00 Å with an average O···N hydrogen bond distance of 2.77(8) Å see Table 3.1.

86 90

700 60

600 50

500 40 Frequency 400 30

Frequency 300 20 200

10 100

0 0 2.5 2.6 2.7 2.8 2.9 3 3 2.5 2.55 2.6 2.65 2.7 2.75 2.8 2.85 2.9 2.95 3 O-H…O H-bond distance (Å) O...N hydrogen bond distance (Å) (a) (b) Figure 3.2 Histogram of hydrogen bonds of (a) homosynthon V and (b) heterosynthon VI retrieved from the CSD.

3.2.2 Features of Hydroxyl···Aromatic Nitrogen Interaction

Phenols (pKa 8-11) are more acidic than aliphatic alcohols (pKa 15-17),

consequently the O-H⋅⋅⋅Narom hydrogen bonds formed between phenols and aromatic

aromatic nitrogen are expected to be stronger than that formed between aliphatic alcohols

and aromatic nitrogen. Phenols and aromatic nitrogens can interact via neutral O-

H⋅⋅⋅Narom interaction to form co-crystals or with proton transfer from the hydroxyl oxygen

to the aromatic nitrogen to form organic salts.39 It has been suggested that proton transfer

39 occurs when the difference in pKa is greater than 2.95. The ΔpKa values in co-crystals

13-20 range from -3.27 to -7.45 (Table 3.2) and consequently the O-H⋅⋅⋅Narom

supramolecular synthons in these compounds would therefore be expected to be neutral

rather than ionic.

Table 3.2 pKa values of components used in co-crystals 13-20

Co-crystal pKa of pKa of ΔpKa component 1 component 2

13 9.40 6.13 -3.27 14 9.40 5.50 -3.90

15 9.74 6.13 -3.61

16 9.74 5.50 -4.24

17 10.33 5.50 -4.83

18 10.33 2.88 -7.45 19 9.45 2.88 -6.57

20 9.14 2.88 -6.26

Structural parameters of ancillary groups, namely the C-N-C angle in the aromatic

nitrogen and C-O bond length in the phenolic moieties can be used to support the neutral

or ionic nature of heterosynthon VI. The C–N–C angle in aromatic nitrogen is known to be sensitive to protonation, the cationic form exhibits higher values (ca. 121°) than that of

the corresponding neutral counterpart (ca. 116°).42-43 Histograms of carbon-oxygen

lengths in neutral and ionic hydroxyl moieties were generated using the CSD and are

presented in Figure 3.2 (only good quality crystal structures: ordered, error-free, non-

polymeric with 3D coordinates determined and R< 7.5%). To distinguish neutral C-OH

from ionic C-O- specific restriction on the oxygen atoms were applied during the CSD

searches. For neutral C-OH bond the hydrogen atom was defined to be bonded to the

oxygen atom; the oxygen atom was defined to be uncharged, and the number of bonded

atoms was set to 2. In the case of ionic C-O- bond, the charge of the oxygen was set to -1

and the number of bonded atoms was set to 1. The 14,235 crystal structures that contain

88 neutral aliphatic hydroxyl moieties exhibit an average bond distance of 1.42(2) Å while the 5,150 entries that contain neutral aromatic nitrogen exhibit an average C-OH bond length of 1.36(2) Å. There are 539 entries that contain aromatic deprotonated hydroxyl moieties which exhibit an average C-O- bond of 1.27(4) Å while the 279 crystal

structures that contain aliphatic deprotonated hydroxyl groups exhibit average C-O- bond

distance of 1.26(3) Å.

a) b)

Figure 3.3 Histograms representing the distribution of carbon-oxygen bond lengths in a) neutral aromatic hydroxyl moieties (b) neutral aliphatic hydroxyl moieties (c) deprotonated aromatic hydroxyl moieties and (d) deprotonated hydroxyl moieties.

89 The neutral nature of supramolecular heterosynthon VI was confirmed by proton location in the difference Fourier map, and structural parameters of the C–N–C angle in the aromatic nitrogen moieties and C–O bond lengths in the phenolic moieties.44-45

3.2.3. Crystal Structure Description

The crystal structure of 1-naphthol46-47 consists of molecules linked by homosynthon V into chains that run parallel to the b axis as shown in Figure 3.4.

Figure 3.4 Crystal packing in 1-naphthol

1-naphthol co-crystallizes with 1,2-bis(4-pyridyl)ethane in the 2:1 ratio to yield

(1-naphthol)2●1,2-bis(4-pyridyl)ethane 13. The molecules interact through symmetric

O-H···Narom hydrogen bond [2.7206(15) Å, 167.03°] to form the expected 2:1 discrete

adduct as shown in Figure 3.5. Such discrete units interact in a zig-zag fashion through

C-H···π interactions along the b axis and π···π stacking between molecules of 1,2-bis(4- pyridyl)ethane in adjacent discrete trimers occurs along the c axis. The C-O bond distance in 13 is 1.351Å and the C-N-C bond angle is 116.43° thus supporting the neutral nature of the interaction. The dihedral angle between the planes of the naphthol ring and

90 that of the pyridyl molecule is 66.28°. Similar interactions are also observed in the

isostructural co-crystal 14.

Figure 3.5 Three component adducts present in the crystal structure of 13.

Figure 3.6 Crystal packing in 13

In the crystal structure of (1-napthol)2 ●trans-1,2-bis(4-pyridyl)ethylene 14, two molecules of 1-naphthol and one molecule of trans-1,2-bis(4-pyridyl)ethylene aggregate as discrete trimeric supramolecular adducts through O-H···Narom hydrogen bond

[2.7350(13)Å, 176.4°]. As is observed in the previous co-crystal such discrete units

interact in a zig-zag fashion through C-H···π interactions and further stabilization is

91 afforded by π···π stacking between molecules of trans-1,2-bis(4-pyridyl)ethylene. The

C-O bond distance is 1.353Å and the C-N-C bond angle is 116.57° . The dihedral angle between the planes of the 1-naphthol and trans-1,2-bis(4-pyridyl)ethylene molecules in

14 is 63.38°.

Figure 3.7 Three component adduct in the crystal structure of 14

Figure 3.8 Crystal packing in 14

Figure 3.9 Crystal structure of 4,4’-biphenol

4,4’-Biphenol is sustained by supramolecular homosynthon V to generate a 2D

supramolecular sheet.48 Hydrogen bonded adducts formed between the combination of

double donors such as biphenols and an equal number of acceptors such as diamines are

anticipated to form chains with the two molecular components alternating along the chain

as is observed in co-crystal 15. 4,4’-biphenol●1,2-bis(4-pyridyl)ethane 15, crystallizes

in a monoclinic system and is refined in centrosymmetric P21/c space group. Both

molecules of 4,4’-biphenol and 1,2-bis(4-pyridyl)ethane reside on centers of inversion.

The 1:1 co-crystal is sustained by VI via symmetric O-H…N H-bonding [2.7459(15)Å,

165.5°] to generate infinite zig zag chains.(Figure 3.10) The C-O bond distance is 1.361Å

and the C-N-C bond angle is 116.57°. Molecules of 1,2-bis(4-pyridyl)ethane can adopt

different conformations as a consequence of the flexibility afforded by the central C-C

bond; in 4,4’-biphenol conformational degrees of rotation is afforded about the central

C-C bonds and the hydroxyl group about the C-O bonds. However molecules of 4,4’-

biphenol and 1,2-bis(4-pyridyl)ethane in co-crystal 15 are planar. 93

Figure 3.10 Crystal structure of 4,4’-biphenol●1,2-bis(4-pyridyl)ethane, 15.

In 4,4’-biphenol●trans-1,2-bis(4-pyridyl)ethylene 16, molecules of 4,4’- biphenol and trans-1,2-bis(4-pyridyl)ethylene reside on centers of inversion. As is seen in co-crystal 15, 16 is sustained by supramolecular heterosynthon VI, via symmetric O-

H⋅⋅⋅Narom H-bonding [2.7384(17) Å, 165.0°] to generate infinite zig zag chains. The neutral nature of the interaction is supported by structural data: the C-O bond distance is

1.358 Å and the corresponding C-N-C angle in 16 is 116.66°.

Figure 3.11 Crystal Packing in 4,4’-biphenol●trans-1,2-bis(4-pyridyl)ethylene, 16 94

Figure 3.12 Crystal Packing in 16, viewed down the b-axis

Co-crystallization of a 1:1 mole ratio of hydroquinone and trans-1,2-bis(4-

pyridyl)ethylene results in the formation of hydroquinone●trans-1,2-bis(4- pyridyl)ethylene 17. Molecules of hydroquinone and trans-1,2-bis(4-pyridyl)ethylene

reside on centers of inversion in 17. The resulting 1:1 co-crystal is sustained by VI

through symmetric O-H⋅⋅⋅Narom hydrogen bonds [O⋅⋅⋅N: 2.7053(18)Å, 167.7°] to form

infinite chains (Figure 3. 5) similar to that seen in MEKWUU, the co-crystal of

hydroquinone and 1,2-bis(4-pyridyl)ethane.15 The C-O bond distance in 17 is 1.369 Å and

the C-N-C bond angle is 116.68° which supports the neutral nature of VI.

Figure 3.13 Crystal structure of hydroquinone● trans-1,2-bis(4-pyridyl)ethylene, 17.

Figure 3.14 Crystal Packing in hydroquinone ● trans-1,2-bis(4-pyridyl)ethylene 17.

Hydroquinone ●tetramethylpyrazine (TMP) 18, was crystallized in the monoclinic crystal system and refined in the P21/c space group. The asymmetric unit consists of a half molecule of TMP and a half molecule of hydroquinone. Both molecules reside on a crystallographic center of inversion. In this 1:1 co-crystal the hydroxyl groups of hydroquinone are hydrogen bonded to TMP via O-H⋅⋅⋅Narom hydrogen bonds

[O⋅⋅⋅Narom: 2.76(2)Å] to generate infinite chains (Figure 3.15). Such chains are translationally related along the b axis.

The C-O bond distance in 18 is 1.369 Å and the C-N-C bond angle is 118.92°.

The hydrogen bond distance observed in this co-crystal is consistent with values observed in other alcohol-aromatic nitrogen structures (mean 2.78(2) Å).

Figure 3.15 Crystal structure of hydroquinone ●TMP, 18

The crystal structure of resorcinol (RESORA03, RESORA13)49-50 is sustained by

supramolecular homosynthon V. There are 16 chemically distinct co-crystals of resorcinol in the CSD,40, 51-58 in these structures resorcinol adopts three different

conformations. Of the three possible conformation, resorcinol –OH groups adopts two

divergent motifs that may form linear chain a or zig zag chain b. The convergent –OH motif c allows resorcinol to build discrete hydrogen bonded adducts rather than infinite

motifs (ABEKUN and TAHVII). This particular feature has found application in forming

discrete adducts in which olefins are brought into close proximity such that 2+2-

cycloaddition is achieved upon photo-irradiation.40-41

97 H H H O O O O O O H H H

a b c

Molecules of resorcinol in (resorcinol)2●(TMP)3 19, adopts conformation c.

Surprisingly, co-crystal 19 crystallizes in 3:2 stoichiometry and exhibits discrete five component adducts rather than the expected 2:2 discrete adducts or chains through O-

H⋅⋅⋅Narom hydrogen bonds. While both hydroxyl groups of resorcinol molecules act as O-

H⋅⋅⋅Narom donors, only one of the nitrogen in the two exterior TMP molecules of the discrete units act as O-H⋅⋅⋅Narom acceptor. The non-participating nitrogen atoms are involved in weak C-H⋅⋅⋅Narom interactions with a distance of 3.612Å and 3.712Å. An analysis of the crystal structure revealed two independent S-shaped discrete units each consists of one independent molecule of resorcinol and two independent TMP molecules, one of the TMP molecule reside on a center of inversion. The molecules in the discrete unit interact through O-H⋅⋅⋅Narom hydrogen bonds [O⋅⋅⋅Narom: 2.787(3) Å, 2.816(3) Å].

The O-H⋅⋅⋅Narom hydrogen bonds in the other discrete unit are 2.777(3) Å and 2.824(3) Å.

Such independent discrete adducts are connected via weak C-H⋅⋅⋅O hydrogen bond. TMP molecules within the five component adducts are involved in weak face to face π-π stacking. The C-O bond distances within this structure are 1.362 Å, 1.369 Å, 1.363 Å and

1.371 Å; the corresponding C-N-C angles are 119.21°, 119.06°, 119.22° and 119.24° respectively.

Figure 3.16 S-shaped discrete unit in the crystal structure 19

The asymmetric unit of 2,7-dihydroxynaphthalene● (TMP)2 20, consists of two

molecules of TMP and a molecule of 2,7-dihydroxynaphthalene.. Similar to co-crystal 19

there is deviation from the expected 1:1 stoichiometry in co-crystal 20. The crystal structure reveals that 20 forms a 1:2 discrete unit in which each 2,7- dihydroxynaphthalene molecule is linked to two TMP molecules through O-H⋅⋅⋅Narom hydrogen bonds of 2.806(3) Å and 2.733(3) Å (Figure 3.17). As in co-crystal 19 only one nitrogen atom on TMP is involved in O-H⋅⋅⋅Narom hydrogen bonding. The other

nitrogen atom is involved in weak C-H⋅⋅⋅N interactions. The C-O bond distances are

1.363 Å and 1.362 Å and the corresponding C-N-C bond angles are 118.62° and 118.10° respectively. π⋅⋅⋅π stacking is also observed 20, the centroid to centroid distance of which is 3.688Å.

Figure 3.17 Discrete three component adduct of 2,7-dihydroxynaphthalene•(TMP)2 20.

Co-crystals 13-20 have been investigated in the context of their reproducibility via grinding, solvent-drop grinding59 and growth from melts. It was observed that whereas solvent drop grinding for 4 minutes was efficient at producing the co-crystals or achieving partial conversion in most cases, the dry grinding approach did not always lead to conversion. As confirmed by PXRD and FTIR analysis, co-crystals 13, 14, 15, 16, 17,

18, 19 and 20 were reproduced via solvent drop grinding. 13, 14, 15, 16, 19 was obtained upon dry grinding for longer periods (8 minutes) whereas a mixture of starting materials was obtained in the case of 18, 19 and 20. Melt experiments also proved to be suitable methodology in obtaining 14, 15 and 18 and a new phase was obtained from attempted melt to produce 13.

3.3. Conclusions

The study herein utilizes a series of co-crystals to demonstrate that the alcohol- aromatic supramolecular heterosynthon VI is favored to the alcohol homosynthon V. Co-

100 crystals 13-20 are sustained by the alcohol-aromatic nitrogen supramolecular

heterosynthon VI. This observation is consistent with the supramolecular heterosynthon

persistency exhibited by the 203/208 (97%) of entries containing only these two moieties

(no competing hydrogen bonding moiety) archived in the CSD. The hydrogen bond lengths in 13-20 correspond to the expected values of a typical O-H⋅⋅⋅ Narom interaction

(Table 3.1) and the structural parameters(C-O lengths and C-N-C angles) of the ancillary

groups suggest a neutral character of VI. Co-crystals 13-20 can be reproduced with little or no solvent via solid-state synthesis.

101 Table 3.3 Crystallographic data and structure refinement parameters for co-crystals 13-20

13 14 15 16 17 18 19 20

formula C32H28N2O2 C32H26N2O2 C12H11NO C24H20N2O2 C28H36N4O4 C14H18N2O2 C36H48N6O4 C26H32N4O2 Crystallization Ethanol Ethanol Ethanol Ethanol Methanol Acetonitrile Acetonitrile Aacetonitrile Solvent MW 472.56 470.55 185.22 368.42 292.33 246.30 628.80 432.56 Monoclinic Monoclinic crystal system Monoclinic Monoclinic Monoclinic Monoclinic Triclinic Monoclinic

space group P21/c P21/c P21/c P21/c P21/c P21/c P-1 P21/c a (Å) 6.961(15) 6.8699(7) 11.6591(16) 11.7712(19) 6.000(2) 7.566(2) 9.0768(11) 15.579(3) b (Å) 25.182(5) 25.450(3) 5.9135(8) 5.9268(9) 17.265(6) 9.218(2) 11.7248(14) 8.5123(19) c (Å) 7.7714(16) 7.6379(2) 14.087(2) 13.954(2) 7.062(2) 10.001(3) 17.443(2) 17.781(4) α (deg) 90 90 90 90 90 90 98.097(2) 90 β (deg) 111.272(4) 110.106(2) 107.618(2) 108.614(3) 92.296(6) 111.328(5) 98.195(2) 93.686(6) γ (deg) 90 90 90 90 90 90 106.019(2) 90 V /Å3 1270.9(5) 1254.0(2) 925.7(2) 922.6(3) 731.0(4) 649.7(3) 1734.1(4) 2353.19

-3 1.235 1.246 Dc/g cm 1.329 1.326 1.328 1.259 1.204 1.221

Z 2 2 4 2 2 2 2 4 3.24- 52.74 5.90-52.74 2θ range 3.66-52.74 3.66-56.76 5.72-52.74 5.78–49.92 2.40 – 52.74 2.62-52.74

2587/163 2560/164 Nref./Npara. 1897/127 2108/128 1493/100 1036/82 6924/415 4809/289

T /K 298(2) 298(2) 100(2) 173(2) 100(2) 100(2) 100(2) 100(2)

R1 [I>2sigma(I)] 0.0455 0.0407 0.0423 0.0489 0.0428 0.0460 0.0656 0.0639

wR2 0.1196 0.1156 0.1027 0.1232 0.0990 0.1079 0.1593 0.1530 GOF 1.062 1.079 1.088 1.048 1.060 1.046 1.040 1.021 Abs coef. 0.077 0.078 0.085 0.085 0.088 0.085 0.080 0.079

102 3.4. Experimental Section

3.4.1. Synthesis of Co-crystals

All reagents were purchased from Aldrich and used without further purification.

Co-crystals 13-20 were prepared by dissolving stoichiometric amounts of starting

materials in an appropriate solvent. Crystals were obtained by slow evaporation of the

solvent at ambient temperature in an unmodified atmosphere and were isolated from

solution before complete evaporation of the solvents.

(1-Naphthol)2●1,2-bis(4-pyridyl)ethane, 13: 1-Naphthol (0.035g, 0.24mmol) and 1,2-

bis(4-pyridyl)ethane (0.022g, 0.12mmol) was dissolved in ethanol. Slow evaporation of

the solution yielded X-ray quality crystals, m. pt. 122-124°.

(1-Naphthol)2●trans-1,2-bis(4-pyridyl)ethylene, 14: 1-Naphthol (0.035g, 0.24mmol) and trans-1,2-bis(4-pyridyl)ethylene (0.021g, 0.12 mmol) was dissolved in 2 mL of ethanol. The solution was left to evaporate slowly at room temperature, m. pt. 126-128°.

4,4’-Biphenol●1,2-bis(4-pyridyl)ethane, 15: To 1,2-bis(4-pyridyl)ethane (0.035g,

0.19mmol) was added 4,4-biphenol (0.035g, 0.19mmol). To the solid mixture was added

ethanol (2 mL) and the solution was heated until dissolved. The solution was then

allowed to slow evaporate in an unmodified atmosphere. After a few days, a precipitate

was observed, collected and dried to give yellow blocks of 15, m. pt. 182-186°.

4,4’-Biphenol● trans-1,2-bis(4-pyridyl)ethylene, 16: Slow evaporation of an ethanol

solution containing trans-1,2-bis(4-pyridyl)ethylene (0.022g, 0.12mmol) and 4,4-

biphenol (0.023g, 0.12mmol) yielded yellow rods of co-crystal 16 after 3 day, m. pt. 235-

240°.

104 Hydroquinone●trans-1,2-bis(4-pyridyl)ethylene, 17: Trans-1,2-bis(4-pyridyl)ethylene

(0.028g, 0.15mmol) and hydroquinone (0.017g, 0.15mmol) was dissolved in methanol (2

mL). After a few days, brown blocks of 17 were obtained, m. pt. 196-198°.

Hydroquinone●tetramethylpyrazine (TMP), 18: Colorless crystals of 18 were obtained

upon slow evaporation of an acetonitrile solution containing tetramethylpyrazine (0.022g,

0.17mmol) and hydroquinone (0.019g, 0.17mmol), m. pt. 185-190°.

(Resorcinol)2●(TMP)3, 19 : A 1:1 mixture of TMP (0.026 g, 0.19 mmol) and resorcinol

(0.020 g, 0.19mmol) was dissolved in acetonitrile. Colorless crystals of 19 were obtained

after two days upon slow evaporation at room temperature, m. pt. 134-137°.

2,7-dihydroxynaphthalene●(TMP)2, 20 : Pale green crystals of 20 were obtained upon

crystallization of 1:1 mixture of TMP (0.010g, 0.07 mmol) and 2,7-dihydroxynaphthalene

(0.012 g, 0.07mmol) from acetonitrile solution.

3.4.1. Co-crystallization via grinding

Stoichiometric amounts of the starting materials were ground with a mortar and pestle for

ca.4 minutes.

3.4.2. Co-crystallization via solvent-drop grinding

Stoichiometric amounts of the starting materials were ground with a mortar and pestle for

ca. 4 minutes with the addition of 10 μL of solvent per 50 mg of co-crystal formers.

3.4.3. Co-crystallization via melting

Stoichiometric amounts of the starting materials were heated until melt and the mixture

was left to crystallize at ambient conditions.

105 All compounds were analyzed by infrared spectroscopy using a Nicolet Avatar

320 FTIR instrument. The melting points were determined on a Mel-temp® apparatus

and are presented in Table 3.4.

Table 3.4 Melting points of co-crystals 13-20 and corresponding starting materials

Co-crystal M. pt of M. pt of M. pt of co-crystal component 1 component 2

(1-naphthol)2●1,2-bis(4-pyridyl)ethane, 13 122-124 96 107-110

1-napthol)2 ●trans-1,2-(bis(4-pyridyl)ethylene, 14 126-128 96 150-153

4,4’-biphenol●1,2-bis(4-pyridyl)ethane, 15 182-186 278 107-110

4,4’-biphenol●trans-1,2-bis(4-pyridyl)ethylene, 16 235-240 278 150-153

Hydroquinone● trans-1,2-bis(4-pyridyl)ethylene, 17 196-198 170 150-153

Hydroquinone ●tetramethylpyrazine (TMP ), 18 185-190 170 90

(Resorcinol)2● (TMP)3, 19, 134-137 110 90

13, 14, 15 and 16 have melting points in between that of the starting materials while 17, 18 and 19 have melting point higher that that of both co-crystal formers.

3.4.2. Single Crystal X-ray Crystallography

Co-crystals 13-20 were examined under a microscope and suitable single crystals

were selected for X-ray diffraction. All single crystal data was collected on a Bruker–

AXS SMART APEX CCD diffractometer with monochromatized Mo Kα radiation (λ =

0.71073 Å) connected to a KRYO-FLEX low temperature device. Data sets for co- crystals 15, 17, 18, 19 and 20 were collected at 100K.Whereas data sets for 13 and 14

was collected at 298K and 16 at 173K. Lattice parameters were determined from least

square analysis, and reflection data were integrated using the program SAINT. Lorentz 106 and polarization corrections were applied for diffracted reflections. In addition, the data

was corrected for absorption using SADABS.60 Structures were solved by direct methods and refined by full matrix least squares based on F2 using SHELXTL.61 Non-hydrogen

atoms were refined with anisotropic displacement parameters. All H-atoms bonded to

carbon atoms, except methyl groups, were placed geometrically and refined with an

isotropic displacement parameter fixed at 1.2 times Uq for the atoms to which they were attached. H-atoms of methyl groups as well as N or O bonded protons were located from

Fourier difference map and refined isotropically based upon the corresponding N or O- atom (U(H)=1.2Uq(N, O)). Crystallographic data for 13-20 are presented in Table 3.3 and

selected hydrogen bond distances are listed in Table 3.5.

Table 3.5 Geometrical parameters of intermolecular interactions for co-crystals 13-20

Co-crystal Interaction d (H···A) /Å d (D···A)/Å θ /º

13 O-H⋅⋅⋅N 1.78 2.7206(15) 176.0 14 O-H⋅⋅⋅N 1.80 2.7350(13) 176.4 15 O-H⋅⋅⋅N 1.86 2.7459(15) 165.5

16 1.81 2.7384(17) 165.0 O-H⋅⋅⋅N 17 O-H⋅⋅⋅N 1.79 2.7053(18) 167.7 18 O-H⋅⋅⋅N 1.79 2.760(2) 166.6 O-H⋅⋅⋅N 2.07 2.816(3) 153.7 19 O-H⋅⋅⋅N 1.86 2.787(3) 156.9 O-H⋅⋅⋅N 1.87 2.777(3) 176.8 O-H⋅⋅⋅N 1.97 2.824(3) 156.6 20 O-H⋅⋅⋅N 1.91 2.806(3) 178.5 O-H⋅⋅⋅N 1.76 2.733(3) 160.0

107 3.5. References Cited

1. Desiraju, G. R.; Crystal Engineering: The Design of Organic Solids, Elsevier,

Amsterdam, 1989.

2. Desiraju, G. R.; Angew. Chem. Int. Ed. Eng. 1995, 34, 2311 b) Walsh, R. B. D.;

Bradner, M. W.; Fleishman, S.; Morales, L. A.; Moulton, B.; Rodriquez-Hernedo,

N.; Zaworotko, M. J. Chem Commun., 2003, 186.

3. Taylor R.; Macrae, C.F.; Acta Crystallogr. 2001, B57, 815.

4. Allen, F. H.; Kennard, O. Chem. Des. Automation News 1993, 8, 31.

5. Allen, F. H.; Kennard, O.; Taylor, R. Acc. Chem. Res., 1983, 16, 146.

6. Allen, F. H. Acta Crystallogr. B 2002, 58, 380.

7. Allen, F. H, Taylor, R. Chem. Soc. Rev., 2004, 33, 463.

8. Jayaraman, A.; Balasubramaniam, V.; Valiyaveettil, S. Cryst. Growth Des. 2006,

6, 150.

9. Aitipamula, S.; Nangia, A.; Thaimattam, R.; Jaskolski, M. Acta Crystallogr.,

2003, C59, o481.

10. Thalladi, V. R.; Smolka, T.; Boese, R.; Sustmann, R CrystEngComm , 2000, 2,

96.

11. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr., 1999,

C55, 2133.

12. Lough, A. J.; Gregson, R. M.; Ferguson, G.; Glidewell, C. Acta Crystallogr., 1999,

C55, 1890.

13. Lavender, E. S.; Ferguson, G.; Glidewell, C. Acta Crystallogr., 1999, C55, 430.

108 14. Zeng, Q.; Wu, D.; Wang, C.; Ma, H.; Lu, J.; Liu, C.; Xu, S.; Li, Y.; Bai, C. Cryst.

Growth Des., 2005, 5, 1889.

15. Friscic T.; MacGillivray L. R Chem. Commun., 2003, 1306.

16. Friscic T.; Drab, D. M.; MacGillivray, L. R. Organic letters, 2004, 6, 4647.

17. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr., 1999,

C55, 2133-2136.

18. Lavender, E. S.; Ferguson, G.; Glidewell, C. Acta Crystallogr., 1999, C55, 430-

432.

19. Ferguson, G.; Glidewell, C.; Lavender, E. S. Acta Crystallogr., 1999, B55, 591.

20. Sokolov, A. N.; Friscic, T.; MacGillivray, L. R. J. Am. Chem. Soc., 2006, 128,

2806.

21. Smolka, T.; Boese, R.; Sustmann, R. Structural Chemistry, 1999, 10, 429.

22. Oswald, I. D. H.; Motherwell, W. D. S.; Parsons, S. Acta Crystallogr., 2005, B61,

46.

23. Bis, J. A.; Vishweshwar, P.; Middleton, R. A.; Zaworotko, M. J. Cryst. Growth

Des., 2006, 6, 1048.

24. Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Molecular

Pharmaceutics, 2007, 4, 401.

25. Benyen A.C.; Coupar, P. I.; Fergusaon, G.; Glidewell, C.; Lough A. J.; Meehan,

P.R.; Acta Crystallogr., 1998, C54, 1515.

26. Nguyen, T. L.; Scott, A.; Dinkelmeyer, B.; Fowler, F. W.; Laugher, J. W. New J.

Chem. 1998, 22, 129.

27. Birada, K.; Zaworotko, M. J.; J. Am. Chem. Soc., 1998, 120, 6431.

109 28. Wheatley, P. S.; Lough, A. J.; Ferguson. G.; Glidewell, C. Acta Crystallogr., 1999,

C55, 1489.

29. Ferguson, G.; Glidewell, C. Gregson, R. M.; Lavender, E.S. Acta Crystallogr.,

1999, B55, 573.

30. Corradi, E.; Meille, S.V.; Messina, M.T.; Metrangalo, P.; Resnati, G. Angew. Chem.

Int. Ed. 2000, 39, 1782.

31. Zakaria, C.M.; Ferguson, G.; Lough, A. J.; Glidewell, C. Acta Crystallogr., 2002,

C58, o1.

32. Caira, M.R.; Horne, A.; Nassimbeni, L.R.; Toda, F. J. Mater. Chem., 1997, 7, 2145.

33. Ferguson , G.; Glidewell C.; Lough, A.J.; McManus, G. D.; Meehan, P.R. J. Mater.

Chem., 1998, 8, 2339.

34. Macgillivray, L. R.; Reid, J. L.; Ripmeester, J.A.; CrystEngComm., 1999, 1.

35. Macgillivray, L. R.; Reid, J. L.; Ripmeester, J.A.; Chem. Commun.., 2001, 1034.

36. Ma, B. q.; Zhang Y.; Coppens, P. Cryst. Growth Des. 2001, 1, 272.

37. Ma, B. q.; Zhang Y.; Coppens, P. Cryst. Growth Des. 2002, 2, 7.

38. Hoger, S.; Morisson, D. L.; Enkelman, V. J. Am. Chem. Soc., 2002, 124, 6734.

39. Haung, K, -S.; Britton, D.; Etter, M. C.; Byrn S.R. J. Mater. Chem., 1997, 7, 713.

40. Macgillivray, L. R.; Reid, J. L.; Ripmeester, J.A.; J. Am. Chem. Soc., 2000, 122,

7817.

41. MacGillivray, L. R. CrystEngComm, 2002, 4, 37.

42. Boenigk, D.; Mootz, D. J. Am. Chem. Soc. 1988, 110, 2135.

43. Cowan, J. A.; Howard, J. A. K.; McIntyre, G. J.; Lo, S. M. F.; Williams, I. D. Acta

Crystallogr. B 2003, 59, 794.

110 44. Majerz, I.; Malarski, Z.; Sobczyk, L. Chem. Phys. Lett. 1997, 274, 361.

45. Brzezinski, B.; Grech, E.; Malarski, Z.; Rospenk, M.; Schroeder, G.; Sobczyk, L. J.

Chem. Res. 1997, 151.

46. Rozycka-Sokolowska, E.; Marciniak, B.; Pavlyuk, V. Acta Crystallogr., 2004,

E60, o884.

47. Robinson, B.; Hargreaves, A. Acta Crys,tallogr., 1964, 17, 944.

48. Jackisch, M. A.; Fronczek, F. R.; Geiger, C. C.; Hale, P. S.; Daly, W. H.; Butler, L.

G. Acta Crystallogr., 1990, C46, 919.

49. RESORA03: Fronczek, F. R. Private Communications, 2001.

50. RESORA13: Bacon, G. E.; Jude, R. J. Z. Kristagr. Kristallgeom., Kristallphys.,

Kristallchem., 1973, 138, 19.

51. Papaefstathiou, G. S.; MacGillivray, L. R.; Organic Letters, 2001, 3, 3835.

52. Kawai, H.; Katoono, R.; Nishimura, K.; Matsuda, S.; Fujiwara, K.; Tsuji, T.;

Suzuki, T. J. Amer. Chem. Soc., 2004, 126, 5034.

53. Pickering M.; Small, R. W. H. Acta Crystallogr., 1982, B38, 3161.

54. Boldog, I.; Rosanov, E. B.; Sieler, J.; Domasevitch, K. V. New J. Chem. 2004, 28,

756.

55. Dideberg, O.; Dupont, L., Campsteyn, H. Acta Crystallogr. 1975, B31, 637.

56. Bosch, E., Schultheiss, N.; Rath, N., Bond, M. Cryst. Growth Des. 2003, 3, 263.

57. Barooah, N.; Sarma, R. J.; Baruah, J. B. Cryst. Growth Des. 2003, 3, 639.

58. Vishweshwar, P.; Nangia, A.; Lynch, V. M. CrystEngComm, 2003, 5, 164.

59. Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 20, 2372.

111 60. SADABS [Area-Detector Absorption Correction]. Siemens Industrial Automation,

Inc.: Madison, WI, 1996.

61. Sheldrick, G. M. SHELXTL University of Gottingen: Germany, 1997

112

4. Delineating the Hierarchy of Supramolecular Heterosynthons: Carboxylic

acid-Aromatic Nitrogen versus Alcohol-Aromatic Nitrogen

4.1. Introduction

Alcohols and carboxylic acids are functional groups that occur commonly in

nature and are well represented in the Cambridge Structural Database (CSD.1-2 Moreover

65% of the top 100 prescription drugs3 and 35 % of those compounds possessing

biological activity in the Merck Index4 contain at least one alcohol or carboxylic acid.

However, despite the prevalence of alcohols and carboxylic acids there are only 71 entries in the CSD that contains an alcohol, an acid and an aromatic nitrogen moiety in

the same structure. As a result reliable information on the relative tendency of formation of the supramolecular heterosynthons based upon existing crystallographic information could not be ascertained. A systematic study of the competition between carboxylic acids and alcohols for aromatic nitrogen was therefore undertaken to determine whether a hierarchy exists with respect to the tendency of formation of the acid-aromatic nitrogen supramolecular heterosynthon III to that of the alcohol-aromatic nitrogen supramolecular

heterosynthon VI.

Each supramolecular heterosynthon in the study has proven to be robust when

compared to the tendency of formation of the corresponding supramolecular

homosynthon. Whereby, the carboxylic acid-aromatic nitrogen supramolecular

heterosynthon III is exhibited in 95% crystal structure containing only an acid and an

113 aromatic nitrogen as compared to 6% of entries that exhibit the carboxylic acid

homosynthon I or II. The alcohol-aromatic nitrogen supramolecular heterosynthon VI exists in 97% crystal structures compared to 17% entries that exhibit the alcohol homosynthon V for molecules comprised exclusively of alcohols and aromatic nitrogen.

Competitive studies involving three moieties have been previously conducted by

Aakeroy et al5-6 and Bis et al.7 Aakeröy et al. presented systematic studies of the

competition between three distinct hydrogen bonding moieties: primary amide, pyridine,

and carboxylic acid. The study involved co-crystals of iso-nicotinamide and a range of

aromatic and aliphatic acids. The generated co-crystals revealed consistent hydrogen

bonding patterns comprised of two robust supramolecular synthons: carboxylic

acid···pyridine heterosynthon III and self-complementary amide homosynthon VIII. The reproducibility of the hydrogen bonded motifs suggests a dominant tendency of formation of the acid···pyridine heterosynthon over the acid···amide heterosynthon, that is formed in acid and amide containing compounds in the absence of pyridines.8-14 The latter study conducted by Bis et al involved alcohol, cyano and aromatic nitrogen moieties. The study involved determining the relative tendency of formation of alcohol- aromatic nitrogen in the presence of competing cyano group. It was found that the alcohol-aromatic nitrogen supramolecular heterosynthon VI occurred reliably in the

presence of the cyano moiety.

In the research presented herein co-crystallization experiments were designed

such that the co-crystal formers contained different permutations of carboxylic acid,

aromatic nitrogen and alcohol as shown in Scheme 4.1. Co-crystal formers were selected

based on the criteria that the molecules had the functional group(s) of interest void of

114 other competing hydrogen bond donors and/or acceptors. These functional group(s) were

also sterically accessible and not involved in intramolecular interactions. The co-

crystallization experiments were designed such that one co-crystal former contained two

of the three moieties (eg. alcohol and acid; or alcohol and aromatic nitrogen; or acid and aromatic nitrogen) and the second possessed the remaining moiety e.g aromatic nitrogen or carboxylic acid or alcohol. Accordingly individual pairs of co-crystal formers were combined as follows: (1) a molecule possessing both an acid and an aromatic nitrogen with molecule containing a hydroxyl group; (2) molecules comprising an alcohol and a

carboxylic acid with those having aromatic nitrogen moieties and (3) molecules

possessing an alcohol and an aromatic nitrogen with molecules containing a carboxylic

acid. This approach is premised on the assumption that a co-crystal will be favored if the

synthon between the co-crystal formers is stronger than the interactions within the pure

component. Consequently a co-crystal is not expected to be formed if a dominant

supramolecular synthon already exists within one of the pure components.

115 If Co-crystal forms

OH··· Narom and or COOH···Narom ?

single crystal XRD OH/COOH1: 4-hydroxybenzoic acid N1: 4-phenylpyridine

If co-crystal forms: COOH···Narom dominant

N/OH1: 3-hydroxypyridine COOH2: benzoic acid

If co-crystal forms: OH···Narom dominant

N/COOH1: nicotinic acid OH1: 1-naphthol

Research Strategy utilized in the competitive studies involving carboxylic acids, alcohols and aromatic nitrogens.

Small organic molecules that contain alcohol, aromatic nitrogen, and carboxylic acid moieties used in this study are shown in Figure 4.1. Co-crystallizations of these

chemicals afforded the following crystalline compounds: (3-hydroxybenzoic acid)2

•.pyrazine 21; 4-hydroxybenzoic acid•1,2-bis(4-pyridinium)ethane 4-hydroxybenzoate

22; : (4-hydroxybenzoic acid)2•tetramethylpyrazine (TMP) 23; 4-hydroxybenzoic acid•

4-phenylpyridine 24; (4-hydroxybenzoic acid)2•pyrazine 25; (4-hydroxybenzoic acid)2

•tetramethylpyrazine acetonitrile solvate 26; 3-hydroxybenzoic acid•(4-phenylpyridine)2

27; 3-hydroxybenzoic acid•1,2-bis(4-pyridyl)ethane 28; 3-hydroxybenzoic acid •

4,4’-bipyridine 29; 3-hydroxybenzoic acid•quinoxaline 30; (3-hydroxybenzoic acid)2•

(tetramethylpyrazine)3 31; 6-hydroxy-2-naphthoic acid•trans-1,2-bis(4-pyridyl)ethylene

32; 4-hydroxybenzoic acid•trans-1,2-bis(4-pyridyl)ethylene 33; 3-hydroxybenzoic

116 acid•trans-1,2-bis(4-pyridyl)ethylene 34; 3-hydroxypyridinium benzoate 35; 3- hydroxypyridinium isophthalate 36.

HO OH HO OH HO OH

OH 1-Naphthol 4,4'-Biphenol Resorcinol Phloroglucinol

N N

N N N N 4-Phenylpyridine Pyrazine 4,4'-Bipyridine N N 1,2-Bis(4-pyridyl)ethane Trans-1,2-bis(4-pyridyl)ethylene N

N Tetramethylpyrazine COOH HOOC COOH HOOC COOH

COOH HOOC COOH

Benzoic acid Sorbic acid Glutaric acid COOH Isophthalic acid Trimesic acid

OH COOH COOH N N N N OH OH COOH 3-Hydroxypyridine 5-Hydroxyisoquinolone 3-Hydroxybenzoic acid OH Nicotinic acid COOH 4-Hydroxybenzoic acid Isonicotinic acid

Figure 4.1 Molecules used in Co-crystallization Experiments

4.2. Results and Discussion

4.2.1. CSD Analysis

A number of supramolecular synthons are possible when all three moieties

(carboxylic acid, alcohol, aromatic nitrogen) exist within the same crystal structure. The possibilities include: a carboxylic acid homosynthon I and/or II, carboxylic 117 acid···aromatic nitrogen supramolecular heterosynthon III, charge assisted verson of III

i.e. IV, alcohol supramolecular homosynthon V, alcohol···aromatic nitrogen

supramolecular heterosynthon VI, alcohol···carbonyl supramolecular heterosynthon VII

(Scheme 4.3).

O O O H O O H O

+ O H N O H N O H O O H O I III IV O H

H OH N OH O OH O C C C C C

V VI VII

Figure 4.2 Possible supramolecular synthons that can form when OH, Narom and COOH are present in the same structure

Of the 71 entries in the CSD that contain all three moieties: 2 entries exhibit carboxylic acid homosynthon I or II, 9 entries contain alcohol homosynthon V, 41

structures exhibit carboxylic acid-aromatic nitrogen spramolecular synthon III and 20

entries exhibit alcohol-aromatic nitrogen supramolecular synthon VI. Furthermore there

exists 10 structures that exhibit both III and VI. In the absence of competing hydrogen bond donors and/or acceptors the total number of entries containing these three moieties decreases to 11.15 Within this subset, GEHROB, SOFHIE and XAPMAC exhibit acid-

aromatic nitrogen heterosynthon III; MOBZUY exhibits both III and V; and HAKVEV

and GUTSAP form acid dimer I and alcohol-aromatic nitrogen heterosynthon VI. The remaining structures BEQWAV, IDUBUF, VEFVEI, VEFVIM and WEPDIF exhibits both III and VI.

118 Herein, a series of compounds that help to evaluate the relative hierarchy of III

and VI is presented and analyzed in the context of supramolecular synthons formed.

Table 4.1 CSD statistics on supramolecular synthons that occur in structures containing only COOH, Narom, and OH Moieties present No. of Supramolecular Structures D···A Mean (σ) in structure structures synthon with synthon [Å] [Å]

COOH···Narom 104 (95%) 2.50-2.90 2.65(3) COOH and Narom 109 O–H···O 6 (5%) O–H···N 203 (97%) 2.50-3.00 2.77(8) OH and N 208 O-H ···O 52 (26%)

COOH···Narom (alc) 9 2.50-2.90 2.65(3) COOH, N and O–H···N 7 2.50-3.00 2.77(8) arom 11 OH O–H···O 2 2.50-3.00 2.65(3)

4.2.2 Features of the O-H⋅⋅⋅Narom interaction

Structural information obtained from single crystal X-ray analysis can be used to determine the extent of proton transfer by analyzing proton location, bond distances of carboxylic or hydroxyl groups and C-N-C bond angles. Neutral carboxylic acids tend to have dissimilar C=O and C-O bond distances that average 1.21(2)Å and 1.31(2)Å 16 respectively whereas deprotonated carboxylates have average C-O bond distances of

1.25(2)Å.16 Likewise neutral phenolic alcohol groups have average C–O bond lengths of

1.36(2)Å. whereas the calculated average for ionic C–O- bond length is 1.28(4)Å.16 The

C-N-C angle within the aromatic nitrogen moiety is also known to be sensitive to

protonation.16-20 and the cationic form typically exhibits higher values (ca. 122(2)°) than

that of the corresponding neutral molecules (ca. 117(2)°). The structural features of the

bond distances and bond angles are used in the analysis of the presented series of

compounds.

119 In the pharmaceutical industry, it is generally accepted that the reaction of an acid

and a base is anticipated to form a salt if the ΔpKa [pKa (base)- pKa (acid)] is greater than

2 or 3.21 This criterion is often used as a guide when choosing appropriate counterions for

+ - salt selection. With respect to neutral COOH⋅⋅⋅Narom and charge-assisted N -H⋅⋅⋅ O

22 hydrogen bonds, Johnson and Rumon suggests that a pKa difference less than 3.75

affords neutral COOH⋅⋅⋅N interactions whereas ΔpKa greater than 3.75 results in proton

transfer. In a recent article however the predictive utility of ΔpKa in the solid state is

23 scrutinized. The authors report that although pKa values tend to be reliable indicators of

salt formation when ΔpKa >3, and likewise co-crystal formation is depicted when ΔpKa <

0, there exists a salt-co-crystal continuum between ΔpKa range of 0 to 3. Within this range the reaction between an acid and a base can result in salt or co-crystal formation or can contain shared protons, or mixed ionization.23 Within the presented series of

compounds, 21, 25 and 30 all have ΔpKa < 0, and based upon structural information and

IR spectroscopy contain neutral components and therefore form co-crystals (Table 4.2).

23, 24, 27, 28, 29, 31, 32, 33 and 34 have ΔpKa values ranging from 0.86 to 2.05 and also

form co-crystals. 35 and 36 however form salts having ΔpKa of 4.31 and 4.98

respectively. Furthermore based upon the ΔpKa argument the yet isolated compounds within the series in which 3-hydroxypyridine and 5-hydroxyisoquinoline are co- crystallized with carboxylic acids are expected to yield salts (See Appendices).

120

Table 4.2 pKa data for 21-36

Δ pKa [pKa pKa (acid) pKa (base) (base)- pKa (acid)]

21 4.08± 0.10 1.00± 0.30 -3.08

22 4.57± 0.10 6.13± 0.10 1.56

23 4.57± 0.10 2.88± 0.50 1.69

24 4.57± 0.10 5.44±0.10 0.87

25 4.57± 0.10 1.00± 0.30 -3.57

26 4.57± 0.10 2.88± 0.50 1.56

27 4.08± 0.10 5.44±0.10 1.36

28 4.08± 0.10 6.13± 0.10 2.05

29 4.08± 0.10 3.27± 0.26 0.81

30 4.08± 0.10 0.59±0.28 -3.49

31 4.08± 0.10 2.88± 0.50 1.20

32 4.34± 0.30 5.50± 0.26 1.16

33 4.57± 0.10 5.50± 0.26 0.93

34 4.08± 0.10 5.50± 0.26 1.42

35 8.51± 0.10 4.2 4.31

4.86± 0.10 4.2 0.66

36 8.51± 0.10 3.53 4.98

4.86± 0.10 3.53 1.33

4.2.3. Crystal Structure Descriptions

The asymmetric unit of 3-hydroxybenzoic acid• pyrazine 21, consists of a half

molecule of pyrazine and a molecule of 3-hydroxybenzoic acid. The resulting 2:1 co-

crystal form trimeric adducts that are sustained by centrosymmetric COOH⋅⋅⋅Narom

121 supramolecular heterosynthon III. Such three component adducts are interconnected via

alcohol-carbonyl supramolecular heterosython VII (Fig. 4.4) As a consequence, the

overall hydrogen-bonding pattern in 21 can therefore be described as a corrugated 2D

network consisting of interconnected trimeric supramolecular adducts that align nearly

perpendicularly with respect to each other. The dihedral angle between the planes parallel to the interacting trimeric adducts is 89.91°.

In addition to spectroscopic evidence, the neutral nature of III is supported by

structural data: the C=O and the C-O bond distances are 1.228 Å and 1.313Å respectively

and the C-N-C angle within the aromatic nitrogen ring is 117.15°. The COOH⋅⋅⋅Narom

hydrogen bond distance (D: 2.675(2) Å) is within the expected range for carboxylic acid- aromatic nitrogen interactions and the dihedral angle formed between the carboxylic acid group and the pyrazine ring is 9.60°.

Figure 4.3 Crystal packing in (3-hydroxybenzoic acid)2 •pyrazine, 21 showing corrugated sheet

122

Figure 4.4 Interdigitation of independent 2D networks in the crystal structure of 21

In the crystal structure of 4-hydroxybenzoic acid●1,2-bis(4-pyridinium)ethane●

4-hydroxybenzoate 22, there is ambiguity with regards to the location of the proton on

one of the two crystallographically independent molecules of 4-hydroxybenzoic acid.

The carbon-oxygen bond distance on this particular molecule of 4-hydroxybenzoic acid is

1.249 Å and 1. 283 Å and the associated C-N-C angle is 119.2°. The O⋅⋅⋅Narom hydrogen

bond distance of 2.546(2) Å is significantly shorter than the average distance for the acid-

aromatic nitrogen interaction [2.65 (3) Å]. This suggest partial proton transfer in which

24 the proton is shared between the Narom atom and the oxygen atom. The C=O and C–O

bond distances in the second independent molecule of 4-hydroxybenzoic acid are 1.237 Å

and 1.308 Å respectively and the associated C-N-C angle is 117.68°. The crystal structure of 22 is sustained by III and IV, alcohol-carbonyl supramolecular heterosynthon VII as

well as alcohol-carboxylate supramolecular heterosynthon. The basic hydrogen bonding

components are the 1:1:1 adduct as shown in Figure 4.5, such adducts are connected via

123 VII to generate corrugated sheets along the bc plane (Figure 4.6). The supramolecular

sheets stack along the a axis as shown in Figure 4.7.

Figure 4.5 Supramolecular synthon in 22

Figure 4.6 Crystal packing of 22, showing corrugated sheet

Figure 4.7 Crystal packing of adjacent 2D networks in 22

124 The crystal structure of (4-hydroxybenzoic acid)2•TMP 23, is sustained by the

carboxylic acid-aromatic nitrogen heterosynthon III [O⋅⋅⋅N: 2.674(6) Å] and the alcohol-

carbonyl (acid) heterosynthon VII [O⋅⋅⋅O: 2.68(5) Å] hydrogen bond. As is observed in

21 and 22, the nitrogen atoms in TMP are hydrogen bonded to carboxylic acids via heterosynthon III. The hydroxyl group and carbonyl on adjacent 4-hydroxybenzoic acid

molecules interacts via heterosynthon VII resulting in an eight component rectangular

grid as shown in Figure 4.8a. The molecules interact to form a hydrogen bonded

herringbone network with an angle of 110° between the planes of 4-hydroxybenzoic acid

and TMP; and 78° between adjacent 4-hydroxybenzoic acid. The hydrogen bond

distances are consistent with that observed from the CSD analysis.

(a) (b)

Figure 4.8 a) Eight membered molecular rectangular grid formed by six 4-hydroxy benzoic acid and two TMP molecules. b) 2-dimensional herringbone network in the crystal structure of (4-

hydroxybenzoic acid)2•TMP co-crystal 23.

125

Figure 4.9 Crystal packing of adjacent 2D networks in 23

21, 22 and 23 are related in terms of their composition, hydrogen bond motifs and

packing modes. The difference in the molecular structure of the components is not large enough to disrupt the 2D corrugated packing mode.

4-hydroxybenzoic acid●4-phenylpyridine 24, contains one molecule of each

component in the asymmetric unit. Analysis of the crystal structure reveals discrete

tetrameric units which are sustained by alcohol-aromatic nitrogen heterosynthon VI

(D: 2.703 (3) Å) as well as carboxylic acid homosynthon I (D: 2.630(3) Å) as shown in

Figure 4.10. The neutral nature of VI is supported by structural data: the C-O (alcohol)

bond distance is 1.352Å and the C–N–C angle within the aromatic nitrogen ring is

116.99°. Stabilization of the structure is also afforded by face to face π-stacking between

neighboring 4-phenylpyridine molecules as shown in Figure 4.12. The centroid to

centroid distances between the aromatic rings are 3.684 Å and 3.862 Å. The torsion angle

126 between the benzyl ring and the pyridyl ring in the 4-phenylpyridine molecule is 41.06° and the dihedral angle formed by 4-phenylpyridine and 4-hydroxybenzoic acid is 66.51°.

Figure 4.10 Crystal structure of 4-hydroxybenzoic acid•4-phenylpyridine 24

Figure 4.11 Crystal packing of 24 showing translationally related carboxylic acid dimer and face to face π-stacked aromatic rings of adjacent 4-phenylpyridine.

The asymmetric unit of the (4-hydroxybenzoic acid)2 •pyrazine 25, consists of

one molecule of 4-hydroxyybenzoic acid lying in a general position and a half molecule

of pyrazine lying on a center of inversion. Similar to that seen in HAKVEV and in the

previous structuure, 24 is sustained by alcohol-aromatic nitrogen supramolecular

127 heterosynthon VI as well as carboxylic acid dimer I. The 4-hydroxybenzoic acid

molecules interact with each other via 2-point recognition acid dimer I and the hydroxyl

portion of the molecule is hydrogen bonded to the pyrazine molecule through O-H⋅⋅⋅Narom hydrogen bonds to generate zig zag chains. Translationally related chains align parallel to

the ab plane. The neutral nature of VI is supported by spectroscopic evidence as well as

structural data: the C–O (alcohol) bond distance is 1.357 Å and the C–N–C angle within

the aromatic nitrogen ring is 116.5(2)°. The O–H···Narom hydrogen bond distance

(D: 2.7739(17) Å) is within the expected range for hydroxyl···aromatic nitrogen

interactions (Table 4.1) and the O-H⋅⋅⋅O hydrogen bond of the centrosymmetric acid dimer is 2.6282 (15) Å.

Figure 4.12 Crystal structure of (4-hydroxybenzoic acid)2 •pyrazine, 25, showing centrosymmetric acid dimers and alcohol-aromatic nitrogen heterosynthons.

Surprisingly the acetonitrile solvate of co-crystal 23, does not exhibit the

carboxylic acid-aromatic nitrogen supramolecular heterosynthon III and the alcohol-acid

supramolecular heterosynthon VII, as seen in the unsolvated form. Rather the crystal structure of (4-hydroxybenzoic acid)2 ●TMP acetonitrile solvate 26, reveals infinite

chains sustained by carboxylic acid dimer I and alcohol-aromatic nitrogen

128 supramolecular heterosynthon VI. The O-H⋅⋅⋅Narom hydrogen bond distance (D:

2.739Å(2) Å) is within the expected range for alcohol-aromatic nitrogen interactions

(Table 4.1) and the hydrogen bond distance of the centrosymmetric carboxylic acid dimer

I is 2.617 Å. The dihedral angle between the 4-hydroxybenzoic acid and the TMP ring is

75.92 Å. The acetonitrile molecule is within the structure is not involved in any strong

hydrogen bond interaction.

Figure 4.13 Crystal structure of (4-hydroxybenzoic acid)2 ●TMP acetonitrile solvate, 26

The asymmetric unit of 3-hydroxybenzoic acid●(4-phenylpyridine)2 27, contains

one molecule of 3-hydroxybenzoic acid and two molecules of 4-phenylpyridine. The

resulting 1:2 co-crystal is sustained by both supramolecular heterosynthon III

(D: 2.596(2) Å) and VI (D: 2.685(2) Å) to generate discrete trimeric adducts. The

observation of a C=O bond distance of 1.220Å and the C-O (acid) of 1.315Å coupled

with the C-N-C bond angle within the aromatic nitrogen molecule of 117.14° suggests a

neutral acid-aromatic nitrogen hydrogen bond. The C-O (alcohol) bond distance of

1.349Å and the C-N-C angle of 116.75° support the neutral nature of the alcohol-

aromatic nitrogen hydrogen bond. Adjacent trimeric adducts within the structure are

129 involved in π-π interactions wherein both face to face π-stacking between adjacent 4- phenylpyridine molecules and edge to face interaction between the 3-hydroxybenzoic acid and the pyridyl molecule is observed. The centroid to centroid distances are 3.726Å and 3.703Å respectively. The dihedral angle between the pyridyl and benzyl ring within the 4-phenylpyridine molecules is 27.88°.

Figure 4.14 Crystal structure of 3-hydroxybenzoic acid.(4-phenylpyridine)2, 27

Figure 4.15 Crystal packing in 3-hydroxybenzoic acid•.(4-phenylpyridine)2, 27.

130 The 1:1 co-crystal of 3-hydroxybenzoic acid•1,2-bis(4-pyridyl)ethane 28, is

sustained by both carboxylic acid-aromatic nitrogen supramolecular heterosynthon III

(D: 2.590(4)Å) and alcohol–aromatic nitrogen supramolecular heterosynthon V

(D: 2.663(4)Å) which alternate to generate infinite chains. The neutral nature of III and

VI is supported by structural evidence: C=O and C-O bond distance of the carboxylic acid group is 1.219 Å and 1.325 Å; the C–N–C angle within the aromatic nitrogen ring is

117.07 and 117.28° respectively and the C-O (alcohol) bond distance was found to be

1.357 Å. Face to face π-stacking between pyridyl moieties in adjacent chains, the

centroid to centroid distance of which are 3.793 Å and 3.721 Å is also observed in this

structure.

Figure 4.16 Crystal structure of 3-hydroxybenzoic acid•1,2-bis(4-pyridyl)ethane, 28.

The asymmetric unit of 3-hydroxybenzoic acid●4,4’-bipyridine 29, consists of

one molecule of 3-hydroxybenzoic acid and one molecule of 4,4’-bipyridine. The 1:1 co- crystal is sustained by both supramolecular heterosynthons III (D: 2.6881(19) Å) and VI

131 (D: 2.7898(19) Å) to generate infinite chains. As is seen in 28, supramolecular heterosynthons III and VI alternate along the length of the chains.

The neutral nature of the interactions is supported by structural evidence: the C=O and C-O bond distance of the carboxylic acid group is 1.216 Å and 1.325 Å respectively; the C–N–C angles within the aromatic nitrogen rings are 116.86 and 117.00° respectively and the C-O (alcohol) bond distance was found to be 1.356 Å. The dihedral angle between the planes of the pyridyl rings in 4,4’-bipyridine is 28.51°.

Figure 4.17 Crystal Packing in 3-hydroxybenzoic acid●4,4’-bipyridine, 29

The crystal structure of 3-hydroxybenzoic acid●quinoxaline 30, reveals infinite chains that are sustained by two supramolecular heterosynthons: carboxylic acid-aromatic nitrogen III and alcohol-aromatic nitrogen VI. As seen in 28 and 29 these interactions alternate along the length of the chain. There are two independent molecules of each component in the asymmetric unit.

The C=O and C-O bond distances of the carboxylic acid groups are 1.217 Å and

1.329 Å; 1.214 Å and 1.335 Å respectively and the C-O (alcohol) bond distances was found to be 1.362 Å and 1.365 Å. π⋅⋅⋅π stacking is also observed within this structure.

132

Figure 4.18 Crystal Packing in 3-hydroxybenzoic acid quinoxaline 30.

The crystal structure of (3-hydroxybenzoic acid)2 ●(TMP)3 31, exhibits both

acid-aromatic nitrogen III and alcohol-aromatic nitrogen VI supramolecular

heterosynthons. Surprisingly 31, does not generate extended chains as is anticipated but rather forms discrete five component adducts as shown in Figure 4.19. Consequently there are two nitrogen acceptor sites that are not involved in any strong hydrogen bond

interactions. These sites are however involved in weak C-H⋅⋅⋅N interactions.

Figure 4.19 Discrete 5-component adduct in the crystal structure of (3-hydroxybenzoic acid)2 ●(TMP)3, 31

133 As seen in the previous co-crystal, 6-hydroxynaphthoic acid.•trans-1,2-(4- pyridyl)ethylene 32, is sustained by both supramolecular heterosynthons III

(D: 2.691(2) Å) and VI ( D: 2.756Å). However unlike 29, 30 and 31, heterosynthons III and VI, alternate in a different manner. Trans-1,2-bis (4-pyridyl)ethylene molecule is hydrogen bonded at both nitrogen acceptor sites to carboxylic acids, then the subsequent trans-1,2-bis (4-pyridyl)ethylene molecule in the chain is hydrogen bonded to alcohols.

This sequence is repeated along the chain. The observed hydrogen bonds are symmetric about the trans-1,2-bis(4-pyridyl)ethylene molecule.

The C=O and C-O (acid) bond distances are 1.216Å and 1.323Å respectively.

The C-N-C angle within the pyridyl rings are 117.34° and 116.4° and the C–O (alc) distance is 1.356Å thus supporting the neutral nature of the O–H···Narom hydrogen bonds.

Figure 4.20 Crystal structure of (6-hydroxynaphthoic acid • trans-1,2-(bis(4-pyridyl)ethylene 32

134

Figure 4.21 Crystal packing in 6-hydroxynaphthoic acid•trans-1,2-bis-(4-pyridyl)ethylene, 32

The asymmetric unit of 4-hydroxybenzoic acid●trans-1,2-bis(4-yridyl)ethylene

33, consists of a molecule of 4-hydroxybenzoic acid and two half molecules of trans-1,2-

bis(4-pyridyl)ethylene. The resulting 1:1 co-crystal is sustained by both supramolecular

heterosynthon III and VI. The components assemble in the alternate manner seen in 32 to

generate zig-zag infinite chains. Molecules of trans-1,2-bis(4-pyridyl)ethylene are

hydrogen bonded at both Narom sites to carboxylic acids, the subsequent trans-1,2-bis(4- pyridyl)ethylene molecule in the chain is hydrogen bonded to alcohols and the sequence repeated along the chain.

The C=O and C-O (acid) bond distances are 1.236Å and 1.316Å respectively.

The C-N-C angle within the pyridyl rings are 116.34° and 117.43° and the C–O (alc) distance of 1.354Å supports the neutral nature of the O–H···Narom hydrogen bonds. π⋅⋅⋅π

stacking is also observed, which affords further stabilization of this structure.

135

Figure 4.22 Crystal packing in 4-hydroxybenzoic acid●trans-1,2-(4-pyridylethylene, 33 showing translationally related zig-zag chains.

The crystal structure of 3-hydroxybenzoic acid●trans-1,2-bis(4- pyridyl)ethylene 34, exhibits both supramolecular heterosynthon III and VI. The 1:1 co- crystal generates chains that hydrogen bond in a manner as seen in co-crystals 32 and 33.

The C=O and C-O bond distances of the carboxylic group are 1.222Å and 1.328 Å respectively whereas the C–O bond distance for the hydroxyl group is 1.361Å. The C-N-

C angle within the pyridyl rings are 117.03° and 116.65° thus supporting the neutral nature of III and VI.

136

Figure 4.23 Crystal packing in 3-hydroxybenzoic acid●trans-1,2 (4-pyridyl)ethylene, 34

The crystal structure of 3-hydroxypyridine is sustained by O-H⋅⋅⋅Narom

supramolecular heterosynthon VI to generate extended chains.25 The 3-hydroxy proton is capable of adopting two conformations: antiplanar or synplanar.26 (The antiplanar

conformation is seen in the pure form.

H O O H

N N antiplanar synplanar

There are twelve compounds in the CSD in which 3-hydroxypyridine is combined

with a carboxylic acid.27 In the reported structures proton transfer result between the acid

and the base to form organic salts. The 3-hydroxy group of the 3-hydroxypyridinium in

IDUNIE, IDUNOK, IDUNUQ, JOJJUN, PAHZAA, VITXUR and YETLUE adopts

137 antiplanar conformation while the synplanar conformation is exhibited by IDUNEA,

KUFBOC, OCAKAF and RACBED.

Attempts to co-crystallize 3-hydroxypyridine and benzoic acid results in proton transfer between the acid and the aromatic nitrogen, thereby generating the charge- assisted hydrogen bonded salt of 3-hydroxypyridinium benzoate 35. The asymmetric unit consists of one ion of each component. The crystal structure exhibits 2-component adducts that is sustained by charge assisted pyridinium-carboxylate supramolecular heterosynthon IV (Figure 4.25a). These adducts are connected orthogonally via alcohol- carboxylate interaction to generate infinite chains. The 3-hydroxyl group of the 3- hydroxypyridinium in 35 adopts the syn-conformation in this structure.

The bond distances for the carboxylate group are 1.286Å and 1.260 Å; and the corresponding C-N-C angle is 121.41°. The dihedral angle between the plane of the carboxylate group and that of the pyridinium ring is 8.05°.

138

(a)

(b)

Figure 4.24 (a) Charge-assisted pyridinium-carboxylate supramolecular heterosynthon IV in 35 (b) Crystal packing in 3-hydroxypyridinium benzoate, 35

The asymmetric unit of 3-hydroxypyridinium isophthalate 36, consists of one

3-hydroxypyridinium ion and one isophthalate ion. Similar to that seen in OCAKAF,28 proton transfer is only observed at one site on the isophthalic acid molecule. 36 is sustained by the charge-assisted pyridinium-carboxylate heterosynthon IV, one point

recognition charge assisted carboxylic acid (OH)-carboxylate interactions and alcohol- carboxylate heterosynthons. As a result of these three significant hydrogen bond interactions supramolecular sheets are generated as seen in Figure 4.25. The 3-hydroxyl group of the 3-hydroxypyridinium in 36 adopts the anti-conformation in this structure.

139

Figure 4.25 Crystal packing in 3-hydroxypyridinium isophthalate 36

The crystal structures of isonicotinic acid and nicotinic acid are sustained by

supramolecular heterosynthon III and generate extended chains.29-30 An analysis of the

CSD yielded no examples of co-crystals containing isonicotinic acid. However there are

five examples of organic salts involving the isonicotinate ion in the CSD31 (Refcodes:

AWUDEB, HAFZIY, PAZHOO, SATLUV and YERXUP). The counter-ions in the

aforementioned compounds are derived from molecules that are either more basic or

acidic than isonicotinic acid. A similar observation is made in the case of nicotinic acid.

Nicotinic acid forms several organic salts 32 and a co-crystal with 4-aminobenzoic acid. 33

Solution and solvent drop grinding34 attempts to co-crystallize isonicotinic acid

and nicotinic acid with a series of alcohols resulted in a mixture of starting materials as evidenced by XRPD. The negative results perhaps is suggesting that the carboxylic acid- aromatic nitrogen supramolecular heterosynthon in the pure nicotinic acids is more dominant than the alcohol-aromatic nitrogen heterosynthon that would exist if a co-crystal were to form.

140 Rationalization of Crystal Structures

3-Hydroxybenzoic acid exists as two polymorphic modifications. Form I exhibits the commonly occurring carboxylic acid dimer I as well as the chain motif of the alcohol homosynthon V, to generate corrugated 2D sheets (Figure 4.26a and b). In the second polymorph the acid dimer motif is abandoned in favor of a new motif which consists of

1-point recognition alcohol homosynthon V and alcohol-carbonyl (acid) interaction VII,

to generate a molecular tape (Fig 4.26b).35 This structural pair illustrates that the same

compound can exist in both centrosymmetric and non-centrosymmetric structures and can perhaps help to explain why different supramolecular motifs are adopted in the structures

containing 3-hydroxybenzoic acid.

141

(a)

(b) Figure 4.26 Crystal structures of the polymorphic forms of 3-hydroxybenzoic acid: (a) Form I and( b) Form II

142 H O H O H O O O a) O O O H H O H H O O O H

N N H O O O H

Chain Type 1 N N H O O O H

H O H O H O H O O O O O O H b) O H O H O H

H O H O O N N O O H O H N N H O O Chain Type 2 O H

Figure 4.27 Chain motifs generated in 21-34 rationalized via synthons occurring in the pure carboxylic acid.

4-Hydroxybenzoic acid is also known to be polymorphic, 36 there is however only

one reported form in the CSD.37 The crystal structure of Form II of 4-hydroxybenzoic acid was determined by exploiting synchrotron X-ray microcrystal diffraction techniques.

38-39 The crystal structure of 4-hydroxybenzoic acid Form I exhibit carboxylic acid dimer

I and alcohol homosynthon V. Similar to that seen in Form I of 3-hydroxybenzoic acid,

the hydroxyl groups engage in forming homosynthon V, constructing chains that extend

through the crystal. The reported crystal structure of Form II of 4-hydroxybenzoic acid

also contains centrosymmetric carboxylic acid dimer I, however there is no interacton

143 between adjacent hydroxyl groups as seen in Form I. Rather the hydroxyl group in Form

II is involved in the formation of alcohol-carbonyl supramolecular heterosynthon VIII,

which serves to link adjacent dimers consequently generating a supramolecular sheet.

It should also be noted that the co-crystals of 3-hydroxybenzoic acid with meta and para nicotinamide also exhibits different supramolecular synthons and crystal packing.5,40 LUNMEM the co-crystal of 3-hydroxybenzoic acid with isonicotinamide

exhibits III and VIII and the hydroxyl group interacts with the carbonyl of the amide moiety. XAQQIQ exhibits alcohol-aromatic nitrogen VI and acid-amide 2-pt recognition

supramolecular synthon X. These structures may perhaps also be rationalized based upon the crystal packing in the pure components.

In summary, sixteen crystal structures were isolated in the study involving the

competition between alcohol and carboxylic acid for aromatic nitrogen. 21-23 were

sustained by carboxylic acid-aromatic nitrogen supramolecular heterosynthon III as well as alcohol-carbonyl(acid) synthon VII, 24-26 exhibited alcohol-aromatic nitrogen supramolecular heterosynthon VI and carboxylic acid dimer I. 27-34 exhibit both acid-

aromatic nitrogen III and alcohol-aromatic nitrogen VI supramolecular heterosynthons

whereas 35 and 36 exhibited the charge-assisted pyridinium-carboxylate supramolecular

heterosynthon IV. Of the eight structure that exhibit both III and VI: 27, 28, 29 and 30

exhibit chain type 1 whereas 31, 32, 33, and 34 exhibit chain type 2 (Figure 4.27) The chain types observed and consequently the crystal structures may be rationalized in terms of the synthons present in the pure carboxylic acids.

144 Table 4.3 Summary of supramolecular synthons present in 21-36

I III IV VI VII

H O O O O OH O C OH N + C O O H N O H N O H C

21 √ √ 22 √ √ √ 23 √ √ 24 √ √ 25 √ √ 26 √ √ 27 √ √ 28 √ √ 29 √ √ 30 √ √ 31 √ √ 32 √ √ 33 √ √ 34 √ √ 35 √ 36 √ *

4.2.4 Methods of Preparation

Co-crystallization experiments were attempted utilizing grinding, solvent-drop grinding and melting techniques. Solvent drop grinding and melt experiments of 3- hydroxypyridinium benzoate 35, 3-hydroxypyridinium isophthalate 36, 3-

hydroxypyridine •sorbic acid, (3-hydroxypyridine)2•glutaric acid and

(3-hydroxypyridine)3•trimesic acid yielded new phases as characterized by XRPD and

DSC. Moreover grinding, solvent drop grind and melt afforded the same phase as

obtained from solution in the case of 35 and 36.

Solution co-crystallization attempts to obtain crystals of: 5-hydroxyisoquinoline •

benzoic acid, 5-hydroxyisoquinoline •sorbic acid, (5-hydroxyisoquinoline)2•glutaric acid

145 and (5-hydroxyisoquinoline)2 • isophthalic acid, were unsuccessful. However as indicated

by XRPD and DSC new phases were obtained upon solvent drop grinding and subsequent melting.

Solution and solvent drop grinding attempts to obtain co-crystals of nicotinic acid and isonicotinic acid with carboxylic acids were unsuccessful; the IR spectroscopy and

PXRD spectra of the solid obtained revealed a mixture of starting materials.

21-34 were also investigated in the context of their accessibility via grinding and

solvent drop grinding methodologies. Initial 4-minute grinds and solvent drop grinds

resulted in a mixture of starting materials in most cases with the exception of 23, 27 and

30. Co-crystals 21, 23, 28, 29, 30 and 31 were reproduced by solvent drop grinding. 29,

30 and 31 was also obtained from the melt. Attempts to reproduce 21, 22, 23 and 25 from the melt resulted in the formation of new phases that differ from the isolated compounds and their respective starting materials.

No proper theory on melting exists to date. However in general para isomers almost invariably have higher melting points than meta isomers the observation is a true solid state effect.41 The series of compounds presented all have melting points that occur

in between that of the initial components and no general correlations with respect to

melting points could be made between the co-crystals of 3-hydroxybenzoic acid versus

those of 4-hydroxybenzoic acid within this series of compounds (Table 4.4).

146

Table 4.4 Melting point comparison for 21-36

M. pt of compounds M. pt of component 1 M. pt of component 2

21 178 199-203 52-55

22 194-198 214-217 107-110 23 150-154 214-217 84-86

24 90-96 214-217 69-73

25 160-164 214-217 52-55

26 178-182 214-217 84-86

27 115-118 199-203 69-73 28 180-184 199-203 107-110

29 176-179 199-203 111-114

30 100-104 199-203 29-32

31 139-142 199-203 84-86

32 184-187 237-241 150-153 33 184-186 214-217 150-153

34 180-184 199-203 150-153

4.3. Conclusions

In summary, the study presented herein involves a series of model co-crystals that adds to the limited information within the CSD related to the frequency of occurrence of supramolecular heterosynthon III in the presence of the competing alcohol functional

group. That both III and VI occurs when an acid, an alcohol and an aromatic nitrogen are

co-crystallized suggests that the COO–H···Narom III hydrogen bond is comparable to the

O–H···Narom hydrogen bond VI. However the crystal structures obtained may be

rationalized based upon the synthons existing in the pure components. Single crystals of 147 3-hydroxypyridinium benzoate, 35 and 3-hydroxypyridinium isophthalate 36, exhibit proton transfer between the carboxylic acid and the aromatic nitrogen and was sustained by charge assisted interaction IV. The charge assisted heterosynthon IV results perhaps as a consequence of the pKa difference existing between the components. The negative results obtained within the series of compounds involving isonicotinic acid and nicotinic acid with alcohols, coupled with the positive results obtained within the series involving

OH/Narom with COOH suggests that the formation of the carboxylic acid-aromatic nitrogen supramolecular heterosynthon III appears to dominate over that of the alcohol- aromatic nitrogen supramolecular heterosynthon VI.

This conclusion is particularly relevant to co-crystals of APIs, since they are relatively complex molecules that often contain either OH or COOH moieties.

Modification of the physicochemical properties that is associated with the co-crystal formation may lead to interesting opportunities toward new formulations for the improved performance of an API.

4.4. Experimental Section

4.4.1. Syntheses

Reagents were purchased from Aldrich and used without further purification.

Single crystals of compounds 21-36 were obtained via slow evaporation of stoichiometric amounts of starting materials in appropriate solvents and were isolated from solution before complete evaporation of the solvents in all cases except 26.

(3-Hydroxybenzoic acid)2 • pyrazine, 21: To 3-hydroxybenzoic acid (0.015 g,

0.13 mmol) was added pyrazine (0.020 g, 0.13 mmol). The solid mixture was dissolved

148 in chloroform (2ml) and the solution was left to evaporate slowly at room temperature.

After 4 days colorless crystals of 21, mp = 178 °C, were observed.

4-Hydroxybenzoic acid•1,2-bis(4-pyridinium)ethane 4-hydroxybenzoate, 22: To

4-hydroxybenzoic acid (0.026 g, 0.22 mmol) was added 1,2-bis(4-pyridyl)ethane (0.020

g, 0.11 mmol) and the mixture dissolved in methanol (2 ml). The solution was allowed to

evaporate at ambient temperature and after 8 days colorless crystals of 22, mp = 194-198

°C, were obtained.

(4-Hydroxybenzoic acid)2•tetramethylpyrazine, 23: To 4-hydroxybenzoic acid

(0.026 g, 0.22 mmol) was added tetramethylpyrazine (0.020 g, 0.11 mmol) and the solid

mixture dissolved in methanol (2ml). The solution was allowed to evaporate to dryness to

obtain crystals of 23, mp = 150-154 °C.

4-Hydroxybenzoic acid•4-phenylpyridine, 24: A solution of 4-hydroxybenzoic

acid (0.015 g, 0.13 mmol) and 4-phenylpyridine (0.020 g, 0.13 mmol) in 2 mL of acetone/ethyl acetate (1:1) solvent mixture was left to evaporate at ambient conditions.

After 3 days, colorless crystals of 24, mp = 90-94°C were obtained.

(4-Hydroxybenzoic acid)2 • pyrazine, 25: To 4-hydroxybenzoic acid (0.041g,

0.30 mmol) was added pyrazine (0.012g, 0.15mmol). The solid mixture was dissolved in acetonitrile (2 ml) and allowed to evaporate undisturbed at room temperature. After 4 days colorless crystals of 25, mp = 160-164°C, were observed.

(4-Hydroxybenzoic acid)2•tetramethylpyrazine acetonitrile solvate, 26: To 4- hydroxybenzoic acid (0.026 g, 0.22 mmol) was added tetramethylpyrazine (0.020 g, 0.11 mmol) and the mixture was dissolved in 2 mL of acetonitrile. After 8 days colorless crystals of 26, mp = 178-182°C, were obtained. 149 3-Hydroxybenzoic acid•(4-phenylpyridine)2, 27: To 3-hydroxybenzoic acid

(0.015 g, 0.13 mmol) was added 4-phenylpyridine (0.020 g, 0.13 mmol) and 2 mL of 1:1

of acetone and ethyl acetate solvent mixture. Slow evaporation of the solution afforded

colorless crystals of 27, mp = 115-118 °C after 3 days.

3-Hydroxybenzoic acid•1,2-bis(4-pyridyl)ethane, 28: To 3-hydroxybenzoic acid

(0.026 g, 0.22 mmol) was added 1,2-bis-(4-pyridyl)ethane (0.020 g, 0.11 mmol) and the

mixture was dissolved in 2 mL of acetone. After 3 days colorless crystals of 28,

mp =180-184 °C, were observed.

3-Hydroxybenzoic acid• 4,4’-bipyridine, 29: To 3-hydroxybenzoic acid (0.031 g,

0.26mmol) was added 4,4’-bipyridine (0.020 g, 0.13 mmol). The solid mixture was

dissolved in 2 mL of methanol and the solution was left undisturbed to evaporate under

ambient conditions. After 12 days yellow needles of 29, mp = 176-179° C, were formed.

3-Hydroxybenzoic acid•quinoxaline, 30: To 3-hydroxybenzoic acid (0.032g,

0.23mmol) was added quinoxaline (0.030g, 0.23 mmol) and 2 mL of ethanol. After 2

days colorless crystals of mp = 100-104°C, were obtained.

(3-Hydroxybenzoic acid)2• (tetramethylpyrazine)3, 31: To 3-hydroxybenzoic

acid (0.020g, 0.14mmol) was added tetramethylpyrazine (0.20 g, 0.14 mmol). The solid mixture was dissolved in 2 mL of acetonitrile and the solution was left undisturbed to evaporate under ambient conditions. After 12 days yellow needles of 31, mp = 139-142

°C, were formed.

6-Hydroxy-2-naphthoic acid•trans-1,2-bis(4-pyridyl)ethylene, 32: To 6-hydroxy-

2-naphthoic acid (0.025g, 0.13 mmol) was added 1,2-bis(4-pyridyl)ethylene (0.024g,

150 0.013 mmol). The solid mixture was dissolved in 2 mL of methanol. After 2 days

colorless crystals of 32, mp = 184-187°C were observed

4-Hydroxybenzoic acid•trans-1,2-bis(4-pyridyl)ethylene, 33: To 4- hydroxybenzoic acid (0.012g , 0.12 mmol) was added trans-1,2-bis(4-pyridyl)ethylene

(0.023g, 0.13 mmol). The solid mixture was dissolved in 2 mL of methanol. After 2 days

colorless crystals of 33, mp = 184-186°C were observed.

3-Hydroxybenzoic acid•trans-1,2-bis(4-pyridyl)ethylene, 34: To 3-

hydroxybenzoic acid (0.013 g, 0.10mmol) was added trans-1,2-bis(4-pyridyl)ethylene

(0.018g, 0.10 mmol). The solid mixture was dissolved in 2 mL of ethanol. After 2 days

colorless crystals of 34, mp = 180-184°C were observed.

3-Hydroxypyridinium benzoate, 35: To 3-hydroxypyridine (0.020g, 0.21 mmol)

was added benzoic acid (0.026g, 0.21 mmol) and 2 mL of a 1:1 methanol and ethanol

mixture. The solution was left to evaporate at ambient temperature and after 8 days

colorless crystals of 35 were obtained.

3-Hydroxypyridinium isophthalate, 36: To 3-hydroxypyridine (0.025g, 0.26 mmol) was added isophthalic acid (0.022g, 0.13 mmol) and the mixture was dissolved in

0.5 mL of dimethylsulfoxide. After 6 days colorless crystals of 36 were observed.

Co-crystallization via grinding: Stoichiometric amounts of the starting materials were

ground with a mortar and pestle for ca.4 minutes.

Co-crystallization via solvent-drop grinding: Stoichiometric amounts of the starting

materials were ground with a mortar and pestle for ca. 4 minutes with the addition of 10

μL of solvent per 50 mg of co-crystal formers.

151 Co-crystallization via melting: Stoichiometric amounts of the starting materials were

heated until melt and the mixture was left to crystallize at ambient conditions.

All co-crystals were analyzed by infrared spectroscopy using a Nicolet Avatar

320 FTIR instrument. The purity of bulk samples was confirmed by X-ray powder

diffraction. Co-crystals were analyzed on a Rigaku Miniflex Diffractometer using Cu Kα

(λ = 1.54056 Ǻ), 30 kV, 15 mA. The data was collected over an angular range of 3° to

40° 2θ in continuous scan mode using a step size of 0.02° 2θ and a scan speed of

2.0º/min. Compounds and were analyzed on Bruker AXS D8 discover X-ray

diffractometer equipped with GADDSTM (General Area Diffraction Detection System), a

Bruker AXS HI-STAR area detector at a distance of 15.05 cm as per system calibration, a

copper source, automated x-y-z stage, and 0.5 mm collimator. Data were collected over

2.1-37.0 2θ range at a step size of 0.02 2θ. Melting points of 21-34 were determined on a

MEL-TEMP® apparatus, and the comparison of the melting points of 21-34 and the

corresponding constituents is summarized in Table 4.4.

4.4.2. Single-crystal X-ray diffraction.

The single crystal x-ray diffraction data were collected on a Bruker–AXS

SMART APEX CCD diffractometer with monochromatized Mo Kα radiation (λ =

0.71073 Å) connected to a KRYO-FLEX low temperature device. Data for 21-36 were

collected at 100 K. Lattice parameters were determined from least square analysis, and

reflection data were integrated using the program SAINT. Lorentz and polarization

corrections were applied for diffracted reflections. In addition, the data was corrected for

absorption using SADABS.42 Structures were solved by direct methods and refined by

152 full matrix least squares based on F2 using SHELXTL.43 Non-hydrogen atoms were

refined with anisotropic displacement parameters. All H-atoms bonded to carbon atoms,

except methyl groups, were placed geometrically and refined with an isotropic

displacement parameter fixed at 1.2 times Uq of the atoms to which they were attached. N or O bonded protons, as well as H-atoms of methyl groups, were located from Fourier difference map and refined isotropically based upon the corresponding N, O or C atom

(U(H)=1.2Uq(N, O)).

Crystallographic data for 21-36 are presented in Table 4.7. and 4.8. and selected hydrogen bond distances are listed in Table 4.5 and 4.6.

153 Table 4.5 Hydrogen Bond Distances and Parameters for 21-36 Hydrogen Bond d (H···A) /Å D (D···A)/Å Θ /º

O-H⋅⋅⋅⋅N 1.74 2.675(2) 169.0 21 O-H⋅⋅⋅ O 1.82 2.7540(19) 176.5

O-H⋅⋅⋅⋅N 1.54 2.590(2) 173.5

O-H⋅⋅⋅⋅O 1.81 2.6455(19) 167.8

22 O-H⋅⋅⋅⋅N 1.72 2.546(2) 177.6

O-H⋅⋅⋅⋅O 1.90 2.7411(19) 171.6

N-H⋅⋅⋅⋅O 1.59 2.546(2) 177.8

O-H⋅⋅⋅⋅N 1.60 2.674(6) 168.2 23 O-H⋅⋅⋅⋅O 1.65 2.680(5) 154.2

O-H⋅⋅⋅⋅O 1.59 2.630(3) 170.4 24 O-H⋅⋅⋅⋅N 1.79 2.703(3) 167.0

O-H⋅⋅⋅⋅N 1.87 2.7739(17) 169.9 25 O-H⋅⋅⋅⋅O 1.76 2.6282(15) 169.6

O-H⋅⋅⋅⋅N 1.92 2.739(2) 163.7 26 O-H⋅⋅⋅⋅O 1.78 2.617(2) 175.4

O-H⋅⋅⋅⋅N 1.64 2.596(2) 166.6 27 O-H⋅⋅⋅⋅N 1.74 2.685(2) 169.3

O-H⋅⋅⋅⋅N 1.48 2.590(4) 172.4 28 O-H⋅⋅⋅⋅N 1.66 2.663(4) 167.8

O-H⋅⋅⋅⋅N 1.76 2.6881(19) 168.0 29 O-H⋅⋅⋅⋅N 1.81 2.7898(19) 175.0

O-H⋅⋅⋅⋅N 1.85 2.720(2) 170.0

O-H⋅⋅⋅⋅N 1.89 2.782(2) 170.6 30 O-H⋅⋅⋅⋅N 1.77 2.699(2) 169.5

O-H⋅⋅⋅⋅N 1.86 2.762(2) 163.1

154 Table 4.6 Hydrogen Bond Distances and Parameters for 21-36 (cont.)

Hydrogen Bond d (H···A) /Å D (D···A)/Å Θ /º

O-H⋅⋅⋅⋅N 1.77 2.673(2) 177.2 31 O-H⋅⋅⋅⋅N 1.81 2.755(2) 162.2

32 O-H⋅⋅⋅⋅N 1.70 2.756(3) 176.7

O-H⋅⋅⋅⋅N 1.71 2.640(2) 172.5

O-H⋅⋅⋅⋅N 1.54 2.617(4) 168.8 33 O-H⋅⋅⋅⋅N 1.79 2.756(4) 163.8

O-H⋅⋅⋅⋅N 1.64 2.6482(16) 168.6 34 O-H⋅⋅⋅⋅N 1.80 2.7358(16) 174.8

N-H⋅⋅⋅⋅O 1.43 2.559(10) 176.1

35 O-H⋅⋅⋅⋅O 1.74 2.569(9) 169.0

N-H⋅⋅⋅⋅O 2.41 3.065(10) 115.1

O-H⋅⋅⋅⋅O 1.76 2.662(3) 165.8

36 O-H⋅⋅⋅⋅O 1.80 2.662(2) 174.0

N-H⋅⋅⋅⋅O 1.74 2.647(2) 172.4

155 Table 4.7 Crystallographic data and structure refinement parameters for compounds 21-36

21 22 23 24 25 26 27 28

formula C9H8NO3 C26H24N2O6 C11H12NO3 C18H15NO3 C9H8NO3 C13H15N2O3 C29H24N2O3 C19H18N2O3

MW 178.16 460.47 206.22 293.31 178.16 247.27 448.50 322.35 crystal system Monoclinic Monoclinic Monoclinic Monoclinic Triclinic Monoclinic Monoclinic Triclinic

space group P21/n P21/c P21/c C2/c P-1 P21/c P21/n P-1 a (Å) 5..2006(11) 7..3666(3) 10.379(3) 26.780(4) 5..9424(9) 11.693(4) 9..2032(16) 7..9810(15) b (Å) 14.568(3) 23.716(3) 10.307(3) 7.4445(13) 6..8175(10) 8.694(3) 20.819(4) 8..9312(17)

c (Å) 10.994(3) 12.5523(15) 10.134(3) 19.471(3) 10.6376(16) 12.722(4) 11.827(2) 11.209(2) α (deg) 90 90 90 90 102.963(3) 90 90 97.585(3) β (deg) 100.450(5) 103.033(2) 110.257(6) 131.101(2) 97.383(2) 94.920(7) 93.487(3) 90.745(4)

γ (deg) 90 90 90 90 100.057(3) 90 90 90.665(4)

V /Å3 819.1(3) 2136.5(4) 1017.0(5) 2925.1(8) 407.16(11) 1288.5(7) 2261.9(7) 791.9(3) -3 1.235 1.432 Dc/g cm 1.347 1.332 1.453 1.275 1.317 1.352

Z 4 4 4 8 2 4 4 2 2θ range 4.70- 50.04 3.44-52.74 4.18 -45.04 4.04-50.14 4.00-52.74 3.50–50.14 3.92 – 52.74 4.60-56.48

1417/118 4356/307 Nref./Npara. 1260/136 2477/199 1635/118 2198/163 4628/307 3126/217

T /K 100(2) 100(2) 100(2) 100(2) 100(2) 100(2) 100(2) 100(2)

R1 [I>2sigma(I)] 0.0418 0.0472 0.0823 0.0495 0.0456 0.0461 0.0534 0.0810 wR 0.1007 0.1082 0.1771 0.1222 0.1213 0.1110 0.1085 0.2240 2 GOF 1.066 1.032 1.063 1.020 1.068 1.037 1.047 1.186 Abs coef. 0.110 0.103 0.099 0.091 0.111 0.092 0.086 0.093

156 Table 4.8 Crystallographic data and structure refinement parameters for compounds 21-36 (cont)

29 30 31 32 33 34 35 36

formula C17H14N2O3 C15H12N2O3 C19H24N3O3 C23H18N2O3 C19H16N2O3 C19H16N2O3 C12H11NO3 C13H11NO5 MW 294.30 268.27 342.41 370.39 320.34 320.34 217.22 261.23

crystal system Triclinic Triclinic Monoclinic Triclinic Triclinic Triclinic Monoclinic Monoclinic

space group P-1 P-1 P21/c P-1 P-1 P-1 Pc P21/n a (Å) 8.1965(12) 7.2850(9) 9.4609(14) 5.9682(8) 6.1928(19) 7.9011(13) 5.007(15) 10.218(5) b (Å) 8.8828(12) 12.1470(15) 17.807(3) 8.7387(12) 6.957(2) 10.3101(16) 9.93(3) 11.001(6) c (Å) 10.3613(15) 14.4319(18) 11.0809(17) 17.938(3) 18.499(5) 10.8629(17) 10.30(3) 10.412(5) α (deg) 72.213(3) 87.837(2) 90 78.473(2) 95.046(6) 114.081(2) 90 90 β (deg) 72.213(2) 85.937(2) 92.184(3) 82.090(3) 94.058(7) 103.883(3) 100.07(9) 99.983(9) γ (deg) 86.773(3) 80.916(2) 90 88.921(3) 103.928(6) 93.041(3) 90 90 V /Å3 685.25(17) 1257.4(3) 1865.5(5) 907.9(2) 767.1(4) 772.8(2) 504(3) 1152.6(10)

-3 1.426 1.417 Dc/g cm 1.219 1.355 1.387 1.377 1.430 1.505

Z 2 4 4 2 2 2 2 4

2θ range 4.82- 49.42 2.84-52.74 4.88 -52.74 2.34-56.36 2.22-50.18 4.40–49.42 5.74 – 50.16 5.48-52.74

2311/199 5006/361 Nref./Npara. 3804/229 3632/253 2508/217 2591/217 607/145 2340/172

T /K 100(2) 100(2) 100(2) 100(2) 100(2) 100(2) 100(2) 100(2)

R1 [I>2sigma(I)] 0.0442 0.0498 0.0576 0.0564 0.0682 0.0416 0.0437 0.0566

wR2 0.1109 0.1194 0.1303 0.1282 0.1366 0.1112 0.0802 0.1359 GOF 1.092 1.058 1.033 1.040 0.999 1.088 0.804 1.038 Abs coef. 0.100 0.101 0.084 0.091 0.095 0.095 0.104 0.117

157 4.5. References Cited

1. Allen, F. H. Acta Crystallogr. 2002, B58, 380.

2. Allen, F. H, Taylor, R. Chem. Soc. Rev., 2004, 33, 463.

3. Web Page, http://www.rxlist.com/top200.htm

4. Merck Index version. 13.4

5. Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. J. Am. Chem. Soc. 2002, 124,

14425.

6. Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2003, 3, 783.

7. Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Molecular

Pharmaceutics ACS ASAP.

8. Leiserowitz, L. Acta Crystallogr. 1976, B32, 775.

9. Leiserowitz, L.; Nader, F. Acta Crystallogr. 1977, 33, 2719.

10. Reddy, L. S.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2004, 4 , 89.

11. Jetti, R. K. R.; Xue, F.; Mak, T. C. W.; Nangia, A. J. Chem. Soc. Perkin Trans. 2

2000, 6, 1223.

12. Melendez, R. E.; Hamilton, A. D. Top. Curr. Chem. 1998, 198, 97 .

13. Steiner, T. Acta Crystallogr. 2001, B57, 103.

14. Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem. Int. Ed. 2001, 40,

3240.

15. CSD Refcodes: GEHROB, SOFHIE, HAKVEV, GUTSAP, BEQWAV,

IDUBUF, VEFVEI, VEFVIM WEPDIF.

16. Bis, J. A.; Zaworotko, M. J. Crystal Growth Des., 2005, 5, 1169.

156 17. Boenigk, D.; Mootz, D. J. Am. Chem. Soc. 1988, 110, 2135.

18. Cowan, J. A.; Howard, J. A. K.; McIntyre, G. J.; Lo, S. M. F.; Williams, I. D.

Acta Crystallogr. 2003, B59, 794.

19. Mootz, D.; Wussow, H. G. J. Chem. Phys. 1981, 75, 1517.

20. Mootz, D.; Hocken, J. Z. Naturforschung B J. Chem. Sci. 1989, 44, 1239.

21. Stahl, P.H.; Wermuth, C. G. ed. Handbook of pharmaceutical salts: properties,

selection, and use; International Union of Pure and Applied Chemistry, VHCA;

Wiley-VCH: Weinheim, New York, 2002.

22. Johnson, S. L.; Rumon, K. A. J. Phys. Chem., 1965, 69, 74.

23. Childs, S. L.; Stahly, G. P.; Park, A. Molecular Pharmaceutics, 2007 ASAP Alert.

24. Li, Z. J.; Abramov, Y.; Bordner, J.; Leonard, J.; Medek, A.; Trask, A. V. J. Am.

Chem. Soc., 2006, 128, 8199

25. CSD Refcode: BIRYIK10: Ohms, U.; Guth, H.; Treutmann, Z.

Kristallogr.Kristallgeom.; Kristallphys., Krystallchem., 1983, 162, 299.

26. Lynch, D. E.; Lad, J.; Smith, G.; Parsons, S. Crystal Engineering, 1999, 2, 65.

27. CSD Refcodes: IDUNEA, IDUNIE, IDUNOK, IDUNUQ, JOJJUN, KUKBOC,

LEJROH, OCAKAF, PAHZAA, RACBED, VITXUR, YETLUE.

28. CSD Refcode OCAKAF: Gao, S.; Liu, J-W.; Huo, L-H., Zhao, H.; Ng, S. W.

Acta Crystallogr., 2004, E60, o1854.

29. ISNICA: Takusagawa, F.; Shimada, A. Acta Crystallogr., 1976, B32, 1925.

30. NICOAC: Wright, W. B.; King, G. S. D. Acta Crystallogr., 1953, 6, 305.

31. CSD Refcodes: AWUDEB, HAFZIY, PAZHOO, SATLUV and YERXUP

157 32. CSD Refcodes: AFECAT, REFFIS, SAQJUP, SATMAC, TAQNUV, XOXCUI,

QEQVIS, HEWWAI

33. CSD Refcode SESLIM: Jebas, S. R.; Balasubramanian, T. Acta Crystallogr.,

2006, E62, o5621.

34. Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 20, 2372.

35. Gridunova, G. V.; Furmanova, N. G.; Struchkov, Yu. T.; Ezhkova, Z. I.;

Grigor'eva, L. P.; Chayanov, B. A. Kristallografiya, 1982, 27(2), 267-72.

36. Kariuki, B. M.; Bauer, C. L.; Harris, K. D. M.; Teat, S. J. Angew. Chem., Int.

Ed., 2000, 39, 4485.

37. CSD Refcode JOZZIH : Heath, E.A.; Singh P.; Ebisuzaki, Y. Acta Crystallogr.,

1992, C48, 1960.

38. Kariuki, B.M.; Bauer, C. L.; Harris, K. D.M.; Teat, S. J. Angew. Chem. Int. Ed.,

2000, 39, 4485.

39. Single Crystal X-ray diffraction data for a microcrystal of Form II 4-

hydroxybenzoic acid was recorded on Staton 9.8 at the Synchotron Radiation

Source (Daresbury Laborotory). Crystal size 0.10 x 0.07 x 0.05 mm3; T = 296(2)

K; λ= 0.68850Å; monoclinic, P21/n; a = 18.66(2) Å, b=3.860(4) Å; c=18.82(3) Å;

β=93.511(6)°; V=1353(3) A3 ; Z = 8. The microcrystal diffraction station

comprises a Siemens SMART CCD detector and goniometer system. (R1=0.131;

Rw=0.365)

40. McMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.; McLaughlin, O.

L.; Zaworotko, M. J. Zeitschrift fuer Kristallographie, 2005, 220(4), 340-350.

41. Gavezzotti, A. J. Chem. Soc., Perkin Transactions 2, 1995, 1399-404. 158 42. SADABS [Area-Detector Absorption Correction]. Siemens Industrial

Automation, Inc.: Madison, WI, 1996.

43. Sheldrick, G. M. SHELXTL University of Gottingen: Germany, 1997.

159

5. Pharmaceutical Co-Crystals of Stavudine

5.1. Introduction H O N O

OH N O

Stavudine

Stavudine [1-(2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)thymine] is a

synthetic thymidine nucleoside analogue with inhibitory activity against HIV/AIDS. A

review of the literature reveals three polymorphic modifications of stavudine.1-4 This includes a monoclinic (Form I), a triclinic (Form II) and an orthorhombic form (Form

III). The crystal structures of all three forms are sustained by amide dimers and alcohol- alcohol interactions as shown in Figure 5. 1 and therefore exhibits persistent supramolecular synthons. These conformational polymorphs5 differ in the three

parameters that are typically used to describe the conformation of the nucleoside

molecule: the geometry of the glycosylic link, the furanose ring puckering and the

orientation of the 5’ hydroxyl group.6 Structural analysis of all three polymorphs have

been reported, several solvates and a hydrate have also been described in the literature.7-12

However we are unaware of any attempts to generate co-crystals of stavudine. In this

chapter we exploit the remarkable diversity afforded by the imide moiety and utilize the

robust three point recognition supramolecular heterosynthon IX, the alcohol−pyridine 160 heterosynthon VI and the acid-amide heterosynthon X to generate pharmaceutical co- crystals of stavudine.

Figure 5.1 Crystal structure of stavudine (Form I)

NH NH 2 2 NH2

N N N N

H N N 2 NH2 H2N N NH2 melamine 2, 4, 6-triaminopyrimidine 2-aminopyridine (2,4,6-TAP) COOH COOH OH

OH salicylic acid 4-hydroxybenzoic acid Schematic of co-crystal formers

161 5.2. Results and Discussion H O H N

O H O O H N N H N

N H O VI O H N

H X IX

The imide moiety exhibits remarkable diversity in terms of its supramolecular chemistry, it is self complementary and capable of forming 3-point, 2-point and 1-point recognition13 supramolecular synthons. Self association typically occurs via two point

recognition coupling such as that seen in pure stavudine. Of the many supramolecular heterosynthons that the imide moiety can engage in synthon IX is one of the more robust.

In fact a database analysis suggests that heterosynthon IX has the highest probability of

occurrence observed in bimolecular hydrogen bonded ring motifs in organic crystals.14

The three-point recognition heterosynthon IX has some analogy with nucleotide

recognition in DNA,15 and has been utilized to generate numerous co-crystals in a

predictable fashion.16-21 An analysis of the Cambridge Structural Database (CSD)22-25

retrieved 74 structures containing both the imide moiety and the 2-aminopyridine

functional groups. Of these, 46 (62%) structures exhibit the three point supramolecular

heterosynthon IX. The hydrogen bond distances of supramolecular synthons VI, XI and

X are presented in Table 5.1.

162

Table 5.1 Geometrical Features of Supramolecular Synthons D···A Supramolecular Supramolecular Mean (σ) Synthon synthon [Å] [Å]

N–H···Oa 2.50-3.25 2.77(8) IX 2.50-3.25 N–H···N 2.78(8 250-315 VI O–H···N 2.50-3.00 2.78(8)

The alcohol-aromatic nitrogen supramolecular synthon VI is a robust, reliable

heterosynthon in crystal engineering, occurring in 682/1453 (47%) entries as compared to

274/1453 (19%) crystal structures that exhibit the alcohol homosynthon V. As shown previously in Chapter 3 heterosynthon VI has been utilized in generating co-crystals in a predictable manner.26-42

5.2.1. Crystal Structure Description

Co-crystallization of a 3:1 mole ratio of stavudine and melamine resulted in the

formation of (stavudine)3•melamine 37. The asymmetric unit of 37 consists of two

melamine and six stavudine molecules. The presence of multiple molecules in the

asymmetric unit has often been associated with identifiable packing problems or

conflict.43-44 Melamine has three 2-aminopyridine recognition sites and stavudine has one

complementary functional group. Therefore it is anticipated that each melamine and three

stavudine molecules complementarily hydrogen bond via robust three-point

2 supramolecular heterosynthon IX [two R 2 (8)] in a trigonal fashion (Figure 5.2a). As is

observed such trigonal four component adducts are hydrogen bonded via stavudine

O−H···O interactions to generate hexagonal sheet parallel to (001) plane (Figure 5.2b).

163 The hexagonal sheets are connected through O−H···O hydrogen bonds between the

layers. The supramolecular sheets stack along the c axis. All the hydrogen bond lengths

and angles are in the normal range (Table 5.1).

(a) (b)

Figure 5.2 (a) Triangular four component supramolecular adduct in co-crystal 37 (b) Hexagonal packing of 3:1 co-crystal of stavudine and melamine, 37

Co-crystallization of a 2:1 mole ratio of stavudine and 2, 4, 6-triaminopyrimidine

(2, 4, 6-TAP) 38, results in the formation of a 1:1:1 crystal structure in which water is

incorporated in the crystal lattice. 38 contains one molecule each of stavudine, 2, 4, 6-

TAP and water present in the asymmetric unit and crystallizes in the orthorhombic P212121 space group. The three point recognition heterosynthon IX is observed, however instead

of the anticipated 2:1 stoichiometry, we observe stavudine O-H⋅⋅⋅N hydrogen bond

(2.7688(19)Å, 167°) to the 2,4,6-triaminopyrimidine at the second potential hydrogen bonding site. As a result right-handed helices are formed through 3-point recognition heterosynthon IX (N-H⋅⋅⋅O 2.947(2) Å, 166.8°; N-H⋅⋅⋅N: 2.945(2), 174.2°, N-H⋅⋅⋅O 164 2.896, 167.4°) and O-H⋅⋅⋅N heterosynthon VI. Subsequently there are two amino groups

NH2 that are not involved in strong H-bond interactions. The hydroxyl groups of adjacent

primary helix are involved in cooperative hydrogen bonding to generate channels parallel

to the a axis as shown in Fig 5.3. The O-H⋅⋅⋅O hydrogen bond distance within the primary

helix is 2.894(2) Å whereas the O-H⋅⋅⋅O hydrogen bond that bridge adjacent helix is

3.095(3) Å.

Figure 5.3 Crystal Packing of 38 showing right handed helices formed through supramolecular heterosynthons VI and IX.

Stavudine also forms a co-crystal with 2 -aminopyridine, 39. The co-crystal

contains one molecule of stavudine and a 2-aminopyridine molecule in the asymmetric

unit. The presence of the hydroxyl group on the conformationally flexible stavudine

molecule precludes the formation of the two point 2-aminopyridine-amide synthon. The

crystal structure reveals that the alcohol group bridges the aminopyridine-amide synthon

as shown in Fig 5.4. Consequently stavudine molecules interact with 2-aminopyridine molecules through terminal O−H···N hydrogen bonds. (2.6715(16) Å, 172.6°) as

165 illustrated in Figure 5.5. Stavudine molecules interact with each other via N−H···O

(2.7549(16) Å, 165.4º) hydrogen bonds to generate infinite chain along the b-axis. The

structure is further stabilized by the bifurcation of the amino groups by adjacent carbonyl

moieties on two different stavudine molecules: one within the chain (N-H⋅⋅⋅O 3.274(17)

Å and the other in the adjacent chain (N-H⋅⋅⋅⋅O 3.2056(18) Å) as a consequence a two

dimensional corrugated supramolecular sheet is generated.

Figure 5.4 Illustrates the supramolecular synthons present in co-crystal 39, the insertion of the hydroxyl group precludes the formation of the two-point recognition amide-2-aminopyridine supramolecular heterosynthon. Please note that portions of the stavudine molecule have been deleted for clarity.

Figure 5.5 Hydrogen bonded infinite chains of stavudine molecules form terminal O−H···N hydrogen bonds with pyridyl moiety of 2-aminopyridine in co-crystal 39.

A recent study involving the association of nucleobases with carboxylic acids led to the complexation of adenine and cytosine with mono and di-carboxylic acids. The

166

authors observed no complexation with guanine, thymine or uracil.45 Herein we report the

co-crystallization of stavudine, a thymine derivative with monocarboxylic acids. A

review of the CSD reveals no examples of two point recognition between an imide and a

carboxylic acid. However based upon our experience exploiting the acid-amide

supramolecular heterosynthon46-47 to generate pharmaceutical co-crystals, stavudine was

co-crystallized with a series of monocarboxylic acids. As anticipated stavudine forms a

1:1 co-crystal with 4-hydroxybenzoic acid 40. The asymmetric unit of 40 contains one

molecule of stavudine and one molecule of 4-hydroxybenzoic acid. Co-crystal 40 is

sustained by the 2-point recognition carboxylic acid-amide supramolecular heterosynthon

X (N-H⋅⋅⋅O 2.814(2) Å, 171.1° and O-H⋅⋅⋅O 2.649(2); 173°). The alcohols of stavudine

and 4-hydroxybenzoic acid forms right handed cooperative helices through O-H⋅⋅⋅O hydrogen bonds48 of 2.831(2) Å and 2.676(2) Å (see Fig 5.6).

Figure 5.6 Carboxylic acid-amide supramolecular heterosynthon in stavudine•4-hydroxybenzoic acid 40

167

Figure 5.7 Crystal packing of stavudine●4-hydroxybenzoic acid, 40

Stavudine also forms a 1:1 co-crystal with salicylic acid 41, however the expected

carboxylic acid-amide heterosynthon X is not observed. Instead stavudine molecules

form one point recognition O-H⋅⋅⋅O hydrogen bonds with salicylic acid molecules. A

further analysis of the crystal structure reveals that stavudine molecules are connected to

each other in a linear fashion through N-H⋅⋅⋅O hydrogen bonds (2.917(2) Å, 164.5°) as shown in Fig 5.8. Adjacent chains of stavudine molecules are linked together by salicylic acid molecules through O-H⋅⋅⋅O hydrogen bonds.

Figure 5.8 Illustrates supramolecular synthons present in stavudine• salicylic acid 41

168 37, 39, 40 and 41 were also investigated in the context of their susceptibility to

solid state preparation i.e grinding and solvent drop grinding. With regards to

stoichiometry and crystal form, 39, 40 and 41 were reproducibly obtained using the

aforementioned methods. Grinding and solvent drop grinding however yielded a mixture

of starting materials in the case of 37. The syntheses of 38, 39, 40 and 41 were also accomplished via slurry conversion of stoichiometric amounts of the starting materials in water. However as was the case with the grinding and solvent drop grinding, a mixture of starting materials result in the case of 37.

It has been demonstrated that solvent drop grinding can invoke polymorphic transformations. A search for crystal forms of 37, 39, 40 and 41 via solvent drop grinding of co-crystal formers involving seven solvents of different polarity: cyclohexane, chloroform, dimethyl sulfoxide, ethyl acetate, methanol, toluene and water, was also conducted. As determined by FT-IR spectroscopy and X-ray powder diffraction only one form that same as was obtained from solution was isolated for co-crystals 37, 38, 40 and

41.

5.3. Conclusions

Five novel forms of stavudine were presented, four co-crystals and a co-crystal

hydrate.These results further illustrate the diversity that may be obtained using a

supramolecular approach with respect to API forms. 37-41 exhibit a range of

supramolecular synthons including: the one point recognition alcohol- aromatic nitrogen

heterosynthon VI, two point recognition acid-amide X as well as three-point recognition

synthon IX. The syntheses of 39, 40 and 41 were also accomplished via solvent-drop

169 grinding49 of the starting material and 38, 39, 40 and 41 was also obtained via slurry

conversion. These results suggests that solid state methodologies such as grinding and

solvent drop grinding; and slurry conversions are viable means for synthesis of

pharmaceutical co-crystals.

5.4. Experimental Section

5.4.1 Synthesis Stavudine was obtained from Transform Pharmaceutical Inc and used as received.

Reagents used to synthesize co-crystals 37-41 were obtained from commercial sources with purity ca. 98% and used as received. Crystals suitable for single crystal X-ray diffractometry were obtained by slow evaporation of the solvent under ambient conditions.

(Stavudine)3•melamine, 37: Stavudine (0.132g, 0.58 mmol) and melamine (0.034g, 0.27

mmol) were dissolved in 2 mL of ethanol/water mixture upon warming. Slow

evaporation of the solvent at room temperature yielded colorless crystals of 37 within 4

days, m. pt: 186-190º.

Stavudine•2,4,6-triaminopyrimidine hydrate, 38: Stavudine (0.078g, 0.35 mmol) and

2,4,6-triaminopyrimidine (0.022 g, 0.17 mmol) was dissolved in 2ml of 1:1 ethanol / water solvent mixture. Slow evaporation of the solvent yielded colorless crystals of 38.

Stavudine •2-aminopyridine, 39: Stavudine (0.040g, 0.18mmol) and 2-aminopyridine

(0.017g, 0.18mmol) were dissolved in 2 mL of 1:1 ethanol/water solvent mixture upon warming. Slow evaporation of the solvent afforded colorless crystals of 39, m. pt = 120-

122°C.

170 Stavudine •4-hydroxybenzoic acid, 40: Stavudine (0.035 g, 0.16 mmol) and 4- hydroxybenzoic acid (0.22 g, 0.16 mmol) was dissolved in ethanol (2 mL). The solution was allowed to evaporate slowly under ambient conditions to yield colorless crystals of

40.

Stavudine• salicylic acid, 41: Stavudine (0.035g, 0.16mmol) and salicylic acid (0.022 g,

0.16 mmol) was dissolved in ethanol (2 mL). The solution was left to evaporate slowly at room temperature to yield colorless crystals of 41.

For grinding experiments: stoichiometric amounts of starting materials were processed for 4 minutes in a mortar and pestle. The resulting powders were analyzed by

IR spectroscopy and X-ray powder diffraction. Solvent-drop grinding and slurry conversion afforded the same phase as that obtained from solution in all cases except 37.

X-ray powder diffraction (XRPD) analyses were conducted on a Rigaku Miniflex diffractometer using Cu Kα radiation (λ=1.540562, 30 kV and 15Ma). The powder data was collected over an angular range of 3° to 40° 2θ in a continuous mode using a step size of 0.02° 2θ and a scan speed of 2°/min. Differential Scanning Calorimetry (DSC) analyses were performed on a TA instruments 2920 differential scanning calorimeter.

The sample cell was equilibrated at 25° and heated under a nitrogen purge at a rate of

10°C/min. Indium metal was used as the calibration standard. Infrared Spectroscopy was conducted using a Nicolet Avatar 320 FTIR.

5.4.2. Single-crystal X-ray diffraction

The single crystal x-ray diffraction data were collected on a Bruker–AXS

SMART APEX CCD diffractometer with monochromatized Mo Kα radiation (λ =

0.71073 Å) connected to a KRYO-FLEX low temperature device. 171 Data for 37-41 were collected at 100 K. Lattice parameters were determined from least

square analysis, and reflection data were integrated using the program SAINT. Lorentz

and polarization corrections were applied for diffracted reflections. In addition, the data

was corrected for absorption using SADABS.50 Structures were solved by direct methods and refined by full matrix least squares based on F2 using SHELXTL.51 Non-hydrogen

atoms were refined with anisotropic displacement parameters. All H-atoms bonded to carbon atoms, except methyl groups, were placed geometrically and refined with an isotropic displacement parameter fixed at 1.2 times Uq of the atoms to which they were attached. N or O bonded protons, as well as H-atoms of methyl groups, were located from

Fourier difference map and refined isotropically based upon the corresponding N, O or C atom (U(H)=1.2Uq(N, O)).

Selected hydrogen bond distances are listed in Table 5.2 and 5.3 and crystallographic

data for 37-41 are presented in Table 5.4.

172 Table 5.2 Geometric Parameters of Intermolecular Interactions for (stavudine)3●melamine, 37 Interaction d (H...A)/ Å D(D...A) /Å θ /°

O-H⋅⋅⋅⋅Oa 2.05 2.900(5) 137.3

N-H⋅⋅⋅⋅Na 1.95 2.905(5) 153.8

O-H⋅⋅⋅⋅Ob 2.02 2.820(4) 165.8

N-H⋅⋅⋅⋅Nb 2.03 2.904(5) 166.5

O-H⋅⋅⋅⋅Oc 2.00 2.830(5) 157.0

N-H⋅⋅⋅⋅Nc 1.91 2.893(5) 150.5

O-H⋅⋅⋅⋅Od 2.09 2.838(4) 134.6

N-H⋅⋅⋅⋅Nd 1.99 2.893(5) 168.7

O-H⋅⋅⋅⋅Oe 1.95 2.734(4) 149.1

N- H⋅⋅⋅⋅Ne 1.91 2.912(5) 166.2

O- H⋅⋅⋅⋅Of 2.11 2.807(5) 132.3

N- H⋅⋅⋅⋅Nf 2.02 2.884(5) 155.2

N-H⋅⋅⋅⋅Oa 1.97 2.913(5) 169.4

N-H⋅⋅⋅⋅Ob 2.24 2.875(5) 131.6

N-H⋅⋅⋅⋅Oc 2.12 2.923(4) 174.5

N-H⋅⋅⋅⋅Od 2.06 2.937(5) 163.9

N-H⋅⋅⋅⋅Oe 2.10 2.933(4) 161.7

N-H⋅⋅⋅⋅Of 2.06 2.972(5) 153.3

N-H⋅⋅⋅⋅Og 2.07 2.915(4) 173.1

N-H⋅⋅⋅⋅Oh 2.03 2.936(5) 143.5

N-H⋅⋅⋅⋅Oi 2.06 2.917(5) 176.2

N-H⋅⋅⋅⋅Oj 1.93 2.898(5) 168.1

N-H⋅⋅⋅⋅Ok 2.11 2.889(5) 168.3

N-H⋅⋅⋅⋅Ol 1.98 2.960(5) 171.7

173

Table 5.3 Geometric Parameters of Intermolecular Interactions for 38-41

Interaction d(Å) D (Å) θ (deg)

38 O-H⋅⋅⋅⋅N 1.91 2.7688(19) 167.0 N-H⋅⋅⋅⋅N 2.10 2.945(2) 174.2 O-H⋅⋅⋅⋅Oa 1.96 2.894(2) 165.6 O-H⋅⋅⋅⋅Ob 2.25 3.095(3) 135.8 N-H⋅⋅⋅⋅Oa 2.09 2.896(2) 167.4 N-H⋅⋅⋅⋅Ob 2.55 3.194(2) 130.8 N-H⋅⋅⋅⋅Oc 2.52 3.356(3) 162.1 N-H⋅⋅⋅⋅Od 2.07 2.947(2) 166.8 N-H⋅⋅⋅⋅Oe 2.29 3.130(2) 156.3 39 O-H⋅⋅⋅⋅N 1.85 2.6715(16) 172.6 N-H⋅⋅⋅⋅Oa 1.89 2.7549(16) 165.4 N-H⋅⋅⋅⋅Ob 2.39 3.2056(18) 151.2 N-H⋅⋅⋅⋅Oc 2.49 3.2745(17) 153.2 40 O-H⋅⋅⋅⋅Oa 1.65 2.676(2) 159.6 O-H⋅⋅⋅⋅Ob 1.59 2.649(2) 173.0 N-H⋅⋅⋅⋅O 1.92 2.814(2) 171.1 O-H⋅⋅⋅⋅Oc 1.96 2.831(2) 174.4 41 O-H⋅⋅⋅⋅Oa 2.08 2.859(2) 157.3 N-H⋅⋅⋅⋅O 1.92 2.917(2) 164.5 O-H⋅⋅⋅⋅Ob 1.78 2.590(2) 163.3 O-H⋅⋅⋅⋅Oc 1.76 2.582(3) 146.2

174

Table 5.4 Crystallographic Data and structure refinement parameters for compounds 37-41

37 38 39 40 41

(C H N O ) C H N O C H N O C H N O C H N O Chemical 10 12 2 4 3 10 12 2 4 10 12 2 4 10 12 2 4 10 12 2 4 • • • • • formula C3H6N6 C4H7N5 • H2 O C5H6N2 C7H6O3 C7H6O3

stoichiometry 3:1 1:1:1 1:1 1:1 1:1 Formula .wt. 798.79 367.38 318.33 362.33 362.33 crystal system monoclinic orthorhombic orthorhombic Monoclinic orthorhombic

space group C2 P212121 P212121 P21 P212121 a (Å) 28.720(4) 7.2074(10) 7.1242(6) 10.3369(18) 7.114(5) b (Å) 16.622(3) 11.9659(17) 13.7996(12) 7.3130(13) 14.460(9) c (Å) 15.900(2) 19.940(3) 15.0163(14) 11.065(2) 16.414(10) α(°) 90 90 90 90 90 β(°) 102.909(3) 90 90 94.918(3) 90 γ(°) 90 90 90 90 90 volume (Å3) 7398.3(19) 1719.7(4) 1476.3(2) 833.3(3) 1688.6(18)

-3 Dcalc ( g cm ) 1.434 1.419 1.432 1.444 1.425 Z 8 4 4 2 4 θ range 1.31-26.37 1.98-26.37 2.71-26.37 1.98-26.37 1.88-26.37 Nref./Npara. 12303/1063 3502/244 3021/214 3192/242 3440/242 T (K) 100 298 100 298 298

R1 0.0643 0.0379 0.0343 0.0389 0.0390

wR2 0.1384 0.0983 0.0851 0.0931 0.0826 GOF 1.038 1.056 1.110 0.999 0.918 abs coef. 0.111 0.110 0.106 0.114 0.112

175 5.5. References Cited

1. Gurskaya, G. V.; Bochkarev, A. V.; Zhdanov, A. S.; Dyatkina, N. B.; Kraevskii,

A. A. Molekulyarnaya Biologiya, 1991, 25, 483.

2. Harte, W. E.; Starrett, J. E.; Martin, J. C.; Mansuri, M. M. Biochem. Biophys.

Res. Commun., 1991, 175, 298.

3. Mirmehrabi, M.; Rohani, S.; Jennings, M. C. Acta Crystallogr., 2005, C61,

o695.

4. Mirmehrabi, M.; Rohani, S.; Murthy, K. S. K.; Radatus, B. Crystal Growth Des.

2006, 6, 141.

5. Bernstein, J. Polymorphism in Molecular Crystals.; Clarendon Press: Oxford,

United Kingdom, 2002.

6. Saenger, W. Principles of Nucleic Acid Structure; Springer-Verlag; New York

1984.

7. Mirmehrabi, M.; Rohani, S.; Jennings, M. C. Acta Crystallogr., 2005, C61,

695.

8. Van Roey, P.; Taylor, E. W.; Chu, C. K.; Schinazi, R. F J. Am. Chem. Soc. 1993,

115, 5365.

9. Gandhi, R. B.; Bogardus, J. B.; Bugay, D. E.; Perrone, R. K.; Kaplan, M. A. Int.

J. Pharm., 2000, 201, 221.

10. Skonezny, P. M.; Eisenreich, E.; Stark, D. R.; Boyhan, B. T.; Baker, Stephen R.

Eur. Pat. Appl. EP 653435 A1, 1995.

11. Radatus, B. K.; Murthy, K. S. K. US 6635753 B1, 2003.

176 12. Viterbo, D.; Milanesio, M.; Hernandez, R. P.; Tanty, C. R.; Gonzalez, I. C.;

Carrazana, M. S.; Rodriguez, J. D. Acta Crystallogr., 2000, C56, 580.

13. Vishweshwar, P.; Thaimattam, R.; Jaskolski, M.; Desiraju, G. R. Chem. Commun.

2002, 1830.

14. Allen, F. H.; Motherwell, W. D. S.; Raithby, P. R.; Shields, G. P.; Taylor, R. New

J. Chem. 1999, 23, 25.

15. Jeffrey.G. A. ; Saeger W.; Springer-Verlag; Berlin 1991.

16. Zerkowski, J. A.; MacDonald, J. C.; Seto, C. T.; Wierda, D. A.; Whitesides, G.

M. J. Am. Chem. Soc. 1994, 116, 2382.

17. Zerkowski, J. A.; MacDonald, J. C.; Whitesides, G. M. Chem. Mater. 1997, 9,

1933.

18. Zerkowski, J. A.; Mathias, J. P.; Whitesides, G. M. J. Am. Chem. Soc. 1994, 116,

4305.

19. Zerkowski, J. A.; Whitesides, G. M. J. Am. Chem. Soc. 1994, 116, 4298.

20. Zerkowski, J. A.; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc. 1992, 114,

5473.

21. Lehn, J. M.; Mascal, M.; DeCian, A.; Fischer, J. J. Chem. Soc., 1990, 479.

22. Allen, F. H.; Kennard, O. Chem. Des. Automation News 1993, 8, 31.

23. Allen, F. H.; Kennard, O.; Taylor, R. Acc. Chem. Res., 1983, 16, 146.

24. Allen, F. H. Acta Crystallogr. 2002, B58, 380.

25. Allen, F. H, Taylor, R. Chem. Soc. Rev., 2004, 33, 463.

26. Jayaraman, A.; Balasubramaniam, V.; Valiyaveettil, S. Cryst. Growth Des. 2006,

6, 150.

177 27. Aitipamula, S.; Nangia, A.; Thaimattam, R.; Jaskolski, M. Acta Crystallogr.,

2003, C59, o481.

28. Thalladi, V. R.; Smolka, T.; Boese, R.; Sustmann, R CrystEngComm , 2000, 2,

96.

29. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr.,

1999, C55, 2133.

30. Lough, A. J.; Gregson, R. M.; Ferguson, G.; Glidewell, C. Acta Crystallogr.,

1999, C55, 1890.

31. Lavender, E. S.; Ferguson, G.; Glidewell, C. Acta Crystallogr., 1999, C55, 430.

32. Zeng, Q.; Wu, D.; Wang, C.; Ma, H.; Lu, J.; Liu, C.; Xu, S.; Li, Y.; Bai, C.

Cryst. Growth Des., 2005, 5, 1889.

33. Friscic T.; MacGillivray L. R Chem. Commun., 2003, 1306.

34. Friscic T.; Drab, D. M.; MacGillivray, L. R. Organic letters, 2004, 6, 4647-50.

35. Glidewell, C.; Ferguson, G.; Gregson, R. M.; Lough, A. J. Acta Crystallogr.,

1999, C55, 2133.

36. Lavender, E. S.; Ferguson, G.; Glidewell, C. Acta Crystallogr., 1999, C55, 430.

37. Ferguson, G.; Glidewell, C.; Lavender, E. S. Acta Crystallogr., 1999, B55, 591.

38. Sokolov, A. N.; Friscic, T.; MacGillivray, L. R. J. Am. Chem. Soc., 2006, 128,

2806.

39. Smolka, T.; Boese, R.; Sustmann, R. Structural Chemistry, 1999, 10, 429.

40. Oswald, I. D. H.; Motherwell, W. D. S.; Parsons, S. Acta Crystallogr., 2005, B61,

46.

178 41. Bis, J. A.; Vishweshwar, P.; Middleton, R. A.; Zaworotko, M. J. Cryst. Growth

Des., 2006, 6, 1048.

42. Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Molecular

Pharmaceutics, 2007, 4, 401.

43. Hao, X.; Chen, J.; Cammers, A.; Parkin, S.; Brock, C. P. Acta Crystallogr, 2005,

B61, 218.

44. Brock C. P.; Dunitz J. D.; Chem Mater., 1994, 6, 1118.

45. Perumalla, S. R.; Suresh, E.; Pedireddi, V. R. Angew. Chem., Int. Ed, 2005, 44,

7752.

46. Fleischman, S. G.; Kuduva, S. S.; McMahon, J. A.; Moulton, B.; Walsh, R. D.

B.; Rodríguez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des. 2003, 3, 909.

47. McMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.; McLaughlin, O. L.;

Zaworotko, M. J. Z. Kristallogr. 2005, 220, 340.

48. Taylor R; Macrae C. F. Acta Crystallogr. 2001, B57, 815-27.

49. Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 20, 2372.

50. SADABS [Area-Detector Absorption Correction]. Siemens Industrial Automation,

Inc.: Madison, WI, 1996.

51. Sheldrick, G. M. SHELXTL University of Gottingen: Germany, 1997.

179

6. Summary and Future Directions

6.1. Summary

When two or more molecules are co-crystallized the following possibilities exist: a physical mixture of the initial components, the formation of polymorphs of either component, solvate or hydrate of either component, a co-crystal, a salt (given appropriate

pKa difference between the components) or a combination of one or more of the

aforementioned. The exterior functional groups present on the target molecule, their

ability to form robust supramolecular synthons, the appropriate co-crystal former,

conformational flexibility of the molecule, mismatched solubility, crystallization conditions and methods of preparation are some factors that will ultimately dictate which of these possibilities occur.

The research presented herein focus upon the identification of reliable robust supramolecular synthons which has become a pre-requisite in the design process of any crystal engineering experiment. This is of importance since it affords a certain level of predictability with respect to anticipated pattern formation in the crystal structure and

facilitates the appropriate selection of co-crystal formers. Specifically, the research presented focus on the identification of reliable hydrogen bonded supramolecular

heterosythons in the generation of co-crystals and ultimately pharmaceutical co-crystals.

Systematic studies combining CSD analysis and model co-crystal experiments have

180 afforded a better understanding of supramolecular synthons in the solid state. In

particular, the knowledge acquired has led to the delineation of the reliability of two

supramolecular heterosynthons namely the carboxylic acid···aromatic nitrogen (III) and alcohol··· aromatic nitrogen (VI) heterosynthons. Specifically structural analysis of

twelve compounds indicate that the carboxylic acid···aromatic nitrogen supramolecular

heterosynthon (III) forms reliably as compared to the carboxylic acid homosynthon I or

II.

Compounds 1-12 formed in predictable stoichiometries in all cases but one, co-

crystal 3, to generate hydrogen bonded discrete, 2D and 3D structures. The co-crystal of

(trimesic acid)2• (1,2-bis(4-pyridyl)ethane)3 12 exhibits concomitant polymorphism.

Form II of which displays anticipated (6, 3) networks. Form I however display (10, 3)-a networks and exhibits the highest level of interpenetration yet observed in an organic or

metal-organic network. The existence of a (10, 3)-a network with such large dimensions

and the inherent modularity of co-crystals illustrates how co-crystals of TMA might be

worthy of further investigation in the context of open framework networks.

Co-crystallization of alcohols with aromatic nitrogen containing molecules

yielded single crystal data for seven co-crystals all of which are sustained by the alcohol-

aromatic nitrogen supramolecular heterosynthon VI. Based on the statistical analysis and

experimental results the formation of the alcohol-aromatic nitrogen supramolecular

heterosynthon appears more dominant to that of the alcohol homosynthon V.

The strategy for the experiments to evaluate the competition existing between

carboxylic acids and alcohols for aromatic nitrogen involved two co-crystal formers

containing different permutation of the functional groups of interest. In an individual

181 experiment two co-crystal formers were combined, one co-crystal former possessed two

of the three moieties (e.g. COOH/Narom) and the second co-crystal former possessed the

remaining moiety (e.g. OH). According to this strategy, the individual pairs of co-crystal

formers are combined as follows: COOH/Narom with OH, COOH/OH with Narom, and

OH/Narom with COOH. Such an approach to delineate the hierarchies existing between

two supramolecular heterosynthons is premised on idea that a co-crystal can result only if

the favored supramolecular heterosynthon is formed between the co-crystal formers.

Conversely, a co-crystal is not expected to be formed if a dominant supramolecular heterosynthon already exists in one of the pure components.

Of the 16 compounds for which single crystal data was obtained, 14 structures were based upon strategy 2 involving COOH/OH with Narom. Of the obtained structures,

co-crystals 21-23 were sustained by carboxylic acid-aromatic nitrogen supramolecular

heterosynthon III as well as alcohol-carbonyl(acid) synthon VII, 24-26 exhibited

alcohol-pyridine supramolecular heterosynthon VI and carboxylic acid dimer I. 27-34

exhibit both acid-pyridine III and alcohol-aromatic nitrogen VI supramolecular

heterosynthons. Solution and solvent drop grinding attempts to obtain co-crystals of

nicotinic acid and isonicotinic acid with carboxylic acids were unsuccessful; the IR

spectroscopy and PXRD spectra of the solid obtained revealed a mixture of starting

materials. Solvent drop grinding and melt experiments involving 3-hydroxypyridine and

5-hydroxyisoquinoline with carboxylic acids yielded new phases as characterized by

XRPD and DSC. Single crystals of 3-hydroxypyridinium benzoate, 35 and 3- hydroxypyridinium isophthalate, 36 obtained within this series exhibited proton

transfer between the carboxylic acid and the aromatic nitrogen and was sustained by

182 charge assisted interaction, IV. The ionic version of III results perhaps as a consequence

of the pKa difference existing between the components. The negative results obtained

within the series of compounds involving isonicotinic acid and nicotinic acid with

alcohols, coupled with the positive results obtained within the series involving OH/Narom with COOH suggests that the formation of the carboxylic acid-aromatic nitrogen supramolecular heterosynthon III appears to dominate over that of the alcohol-aromatic

nitrogen supramolecular heterosynthon VI.

The supramolecular organization in crystal structures of four co-crystals and a co- crystal hydrate of stavudine formed by co-crystallization with 2- aminopyridines and

carboxylic acids was presented. Stavudine exhibits a range of 1-point, 2-point and 3-point

recognition heterosynthons via O-H⋅⋅⋅N, O-H⋅⋅⋅O and N-H⋅⋅⋅O interactions to generate

pharmaceutical co-crystals. The co-crystals of stavudine further illustrate the diversity

that may be obtained using a supramolecular approach with respect to API forms.

The susceptibility of co-crystals toward method of preparation alternative to

solution was also evaluated. Methods of preparation included growth from melt, grinding

and solvent-drop grinding. The results suggest that solid state methodology are viable

means of synthesizing co-crystals, in most instances the same phase was obtained as that

from solution. Grinding and solvent drop grinding approaches to supramolecular

synthesis is highly relevant in the context of green chemistry. In general the solvent drop

grinding technique has proven to be a reliable technique for the reproducible formation of

multi-component phases requiring less time at achieving conversion than grinding and

consequently may form the basis of an initial co-crystal screening regiment. With respect

to growth from melts sublimation or decomposition of the components need to be taken

183 into consideration when large difference in melting point exists between the initial

components.

The ultimate goal of crystal engineering is the understanding of intermolecular

interactions in an effort to design novel crystalline solids for functional applications. The

presented research has contributed to the overall progress of the field of crystal

engineering by facilitating a better understanding of hydrogen bonded supramolecular

synthons. By combining statistical analysis obtained from the CSD analysis and model

co-crystals studies crystal engineering of pharmaceuticals is feasible.

Physical and chemical properties are intrinsically dependent on molecular arrangement within the crystal structure. Consequently the application of principles of crystal engineering towards API’s is inherently related to the modification of their physicochemical properties. That pharmaceutical co-crystal represents a significant opportunity in the context of drug development and intellectual property consideration is

without question however the role of pharmaceutical co-crystal within the pharmaceutical

industry still remains to be explored. Several foreseeable challenges exists including scale

up, property evaluation of the co-crystalline material, issues related to regulatory

procedures, etc.

6.2. Future Directions

Attempts to identify reliable supramolecular synthons have for the most part been

confined to commonly occurring functional groups such as acids, amides, aromatic

nitrogen, alcohol etc. However further investigation of the reliability of supramolecular

synthons and hierarchies in a competitive environment may be applied to a wider range

184 of hydrogen bonding and halogen bonding moieties.

The focus of the presented research has concentrated on the competition between

two supramolecular synthons, perhaps investigation of the competition of various

hydrogen bonds in the presence of three, four, or even more functional groups should be

addressed as well. Great strides have been made with respect to the generation of binary

co-crystals especially those involving common functional groups, however there is a wide landscape for the formation of ternary or quaternary co-crystals, that remains largely unexplored.

In the context of pharmaceutical co-crystals, the choice of co-crystal formers should be expanded to utilize pharmaceutically acceptable molecules including excipients already utilized in the formulation process. Thus far, there have been limited reports on the physicochemical performance of pharmaceutical co-crystals as compared to the parent API. Consequently the evaluation of physicochemical properties of pharmaceutical co-crystal is an important area for additional research.

Milling or grinding has long been utilized in the pharmaceutical industry as an effective method of particle size reduction. Many bulk properties such as, flowability bulk density, mixing ability, segregation of mixed materials, bulk density etc. are related to particle size. The determination of bulk properties as a consequence of the method of preparation specifically grinding and/or solvent drop grinding also needs to be addressed.

Additionally, there exists a viable opportunity to apply the solvent-grind and grinding

technique towards initial screening and ultimate large scale preparation of pharmaceutical

co-crystals. A temperature regulated High Throughput (HT) grinding or solvent grind

screen can potentially lead to the isolation of new phases-polymorphs, co-crystals, salts-

185 that may not be viable in a tradition HT crystallization screen.

The phenomenon of polymorphism has long attracted attention, in the case of pharmaceuticals the effect range from issues related to bioavailability to intellectual property. Exhaustive screen involving an HT approach during the preformulation stages could provide more insight toward better understanding the phenomenon and evaluating its frequency. In the context of pharmaceutical co-crystals addressing whether or not pharmaceutical co-crystals are more or less prone to polymorphism may lead to important scientific and intellectual property implications. Additionally, the origins of the polymorphism in pharmaceutical co-crystals and co-crystals in general perhaps require further investigation.

The multi-disciplinary nature of crystal engineering may be expanded to address other molecular targets, such as nucleobases, proteins and molecules that mimic biologically active compounds etc. Recombinant DNA technology produces a large number of proteins and protein products however these solids are typically produced by precipitation or lyophillization and tend in most cases to be amorphous or partially amorphous. Consequently the stability of protein pharmaceutics presents a problem that may be addressed by applying crystal engineering. The approach towards such biomolecular co-crystals may be multi-fold addressing issues of stability as well as providing models for drug design, and their binding interactions in the solid state. Other molecular targets that would also prove attractive and amenable for study include: molecules with high polarizability to generate new classes of non-linear-optical materials; explosives or propellants with the potential to reformulate and enhance thermal stability etc; agrichemicals and volatile organics. The exploration and crystal engineering of

186 hydrogen bonded 2D and 3D polymers and consequently the use of the hydrogen bonded synthons as precursors to a range of solid state synthetic reaction are other areas that still remain to be chartered.

187

Appendices

188 Appendix 1. Experimental Data for (benzoic acid)2•1,2-bis(4-pyridyl)ethane 1.

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of (benzoic acid)2•1,2-bis(4-pyridyl)ethane 1

100 ts501d bipethane_benzoic acid

94 %T 93

3000 2000 1000 Wavenumbers (cm-1)

189 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

2500

2000

1500

1000

Relative Intensity Relative Simulated benzoic acid_bipethane 500 benzoic acid

bipethane 0

0 5 10 15 20 25 30 35 40 2-theta/deg

190

400

350

300

250

200

150

Relative Intensity 100 melt

50 solvent grind

0 grind

0 5 10 15 20 25 30 35 40 2-theta/deg

Polymorphism screen data for (benzoic acid)2 •1,2-bis(4-pyridyl)ethane, 1. X-ray powder diffraction (XRPD) patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

600

500

400

300

Relative Intensity 200

100

0 5 10 15 20 25 30 35 40 2-theta/deg

- trace peaks from benzoic acid.

Incomplete conversion as evidenced by XRPD, resulting in a mixture of co-crystal and trace amounts of starting materials-only one form obtained.

191 Appendix 2. Experimental Data for (benzoic acid)2 • trans-1,2-bis(4-pyridyl)ethylene 2

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of (benzoic acid)2 •trans-1,2-bis(4-pyridyl)ethylene 2

ts501e bipethylene_benzoic acid 100

94 1653.17

92 836.85 1559.46 1448.41 955.73 668.67 %T 90 1670.45 1583.24 1416.56 1120.71 976.84

88 1308.94 686.58 660.04 1168.44 796.79 1600.62

86 1204.88 822.58 1068.32 84 1014.35 1272.00 82

3000 2000 1000 709.82 Wavenumbers (cm-1)

192

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1800

1600

1400

1200

1000

800 Relative Intensity 600 simulated benzoic acid _bipethylene 400

bipethylene 200

benzoic acid 0

0 5 10 15 20 25 30 35 40 2-theta/deg

193 500

400

300

200 Relative Intensity

melt 100 solvent grind

0 grind

0 5 10 15 20 25 30 35 40 2-theta/deg

Polymorphism screen data for (benzoic acid)2 • trans-1,2-bis(4-pyridyl)ethylene, 2.

X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

800

600

400 Relative Intensity Relative

200

0 0 5 10 15 20 25 30 35 40 2-theta/deg

Incomplete conversion as evidenced by XRPD, resulting in a mixture of co-crystal and starting materials- only one form obtained.

194 Appendix 3. Experimental Data for benzoic acid •4,4’-bipyridine, 3

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of benzoic acid •4,4’-bipyridine 3. 100

95 1449.08 689. 29 1581.91 94 1026.05 1698.55 615 70 1172.30 1116.88

93 1405.94 1597.89

92 1313.66 1211.60 1005.79 %T ransmittance 91 806. 53 1061.56

90 1269.03 89

87 626.33

4000 3000 2000 1000 715. 53 Wavenumbers (cm-1)

195 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1800

1600

1400

1200

1000

800 Relative Intensity Relative 600 simulated bezoic acid 400 _4,4'-bipy

benzoic acid 200

0 4,4-bipy

0 5 10 15 20 25 30 35 40 2-theta/deg

196 900

800

700

600

500

simulated benzoic acid 400 _4,4'-bipy Relative Intensity

300 solvent grind

200 grind

100

0 melt

0 5 10 15 20 25 30 35 40 2-theta/deg

Polymorphism screen data for benzoic acid •4,4’-bipyridine, 3 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

500

400

300 water

DMSO

200 methanol Relative Intensity ethyl acetate

100 chloroform

toluene

0 cyclohexane

0 5 10 15 20 25 30 35 40 2-theta/deg

197 Polymorphism screen data for 2:1 (benzoic acid)2 •4,4’-bipyridine

500

400

300

Relative Intensity 200

100

0 5 10 15 20 25 30 35 40 2-theta/deg

Solvent drop grind screen of a 2:1 mole ratio of benzoic acid and 4,4’-bipyridine reveals a new phase that is different from the 1:1 co-crystal 3

198 Appendix 4. Experimental Data for sorbic acid•1,2-bis(4-pyridinium)ethane sorbate 4

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of sorbic acid•1,2-bis(4-pyridium)ethane sorbate 4

102

100

94 1686.04

%T 92 1068.64 1643.52 1327.72 1604.69

90 1191.82 1146.25 88 835.55

86 1250.32 1002.44

3000 2000 1000 Wavenumbers (cm-1)

199 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

4000

3500

3000

2500

2000

Relative Intensity Relative 1500

1000 simulated sorbic acid _bipethane xtal

500 sorbic acid

0 bipethane

0 5 10 15 20 25 30 35 40 2-theta/deg

200 150

solvent grind sorbic 100 acid_bipethane

melt sorbic 50 acid_bipethane Relative Intensity

grind sorbic 0 acid_bipethane

0 5 10 15 20 25 30 35 40 2-theta/deg

Polymorphism screen data for sorbic acid •1,2-bis(4-pyridinium)ethane sorbate, 4. X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

500

water 400

DMSO

methanol 300

ethyl acetate Relative Intensity Relative

chloroform 200

toluene

cyclohexane 100

0 5 10 15 20 25 30 35 40 2-theta/deg

201 Appendix 5. Experimental Data for (naproxen)2 •trans-1,2-bis(4-pyridyl)ethylene 5

Infrared Spectrum and X-ray powder diffraction pattern of (naproxen)2 •trans-1,2-bis(4- pyridyl)ethylene 5

102

100

%Transmitt ance 90

82 4000 3000 2000 1000 Wavenumbers (cm-1)

10000

8000

6000 Intensiity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

202

2400

2000

1600

Intensity 1200

800 co-xxtals

400 trans-1,2-bis(4-pyridyl) ethylene naproxen 0

0 5 10 15 20 25 30 35 40 2-theta/deg

250

200

150 xtals

solvent grind 100 Relative Intensity Relative

50 melt

0 grind

0 5 10 15 20 25 30 35 40 2-theta/deg

203

Polymorphism screen data for (naproxen)2•trans-1,2-bis(4-pyridyl)ethylene, 5. X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

300

200

Relative Intensity 100

0 5 10 15 20 25 30 35 40 2-theta/deg

204 Appendix 6. Experimental Data for glutaric acid •1,2-bis(4-pyridyl)ethane, 6

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of glutaric acid •1,2-bis(4-pyridyl)ethane, 6.

101 ts502c glutaric acid_bipethane

100

95 1562.80

%T 94 1212.96 1375.56 876.01 93

92 759.36 1705.96 812.17 1270.66 1607.42 1414.18

91 1065.38 1014.09

90 1176.33 89

3000 2000 1000 827.74 Wavenumbers (cm-1)

205 10000

8000

6000 intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

500

400

300 Simulated glutaric acid _bipethane

200 Grind Relative Intensity

100 Solvent grind

Melt 0

0 5 10 15 20 25 30 35 40 2-theta/deg

206

Polymorphism screen data for glutaric acid •1,2 (4-pyridyl)ethane, 6 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

600

500

400 water

300 DMSO methanol

Relative Intensity ethyl acetate 200 chloroform

toluene 100 cyclohexane

0 5 10 15 20 25 30 35 40 2-theta/deg

207 Appendix 7. Experimental Data for glutaric acid• trans-1,2-bis(4-pyridyl)ethylene, 7

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of glutaric acid trans-1,2-bis(4-pyridyl)ethylene, 7.

ts502d bipethylene_glutaric acid 100

88 1722.82 639.05 1561.21 %T

86 1285.83 1411.84 972.26 955.80 760.63 84 1601.05 1260.64 878.85

82 1179.80 1063.85 1016.14 80 560 76 78

76 824.02

74 3000 2000 1000 Wavenumbers (cm-1)

208 10000

8000

6000

Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

2500

2000

1500

1000 Relative Intensity

simulated glutaric acid 500 _bipethylene xtal glutaric acid

0 bipethylene

0 5 10 15 20 25 30 35 40 45 2-theta/deg

209

900

800

700

600

500

400 Relative Intensity Relative 300

200 melt

100 grind

0 solvent grind

0 5 10 15 20 25 30 35 40 2-theta/deg

Polymorphism screen data for glutaric acid •trans-1,2 (4-pyridyl)ethylene, 7. X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

700

600

500

400 water

300 DMSO Relative Intensity 200 methanol ethyl acetate 100 chloroform toluene 0 cyclohexane

0 5 10 15 20 25 30 35 40 2-theta/deg

Solvent drop grind screen results in only one form as evidenced by XRPD.

210 Appendix 8. Experimental Data for oxalic acid•tetramethylpyrazine, 8

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of oxalic acid•tetramethylpyrazine, 8.

ts436a tetramethylpyrazine_oxalic acid 105

100

90 619 90

85 2852.64 1615.59

80 807. 96 2923.63 1363.24 1451.44

75 1272.56 %T ransmittance 70 989. 84

65 1716.79

60 685 04 55 697. 84 1184.20

3000 2000 1000 Wavenumbers (cm-1)

211 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1400

1200

1000

800

600 Relative Intensity Relative 400 Simulated oxalic acid _TMP

200 TMP oxalic acid Fom II

0 oxalic acid Form I

0 5 10 15 20 25 30 35 40 2-theta/deg

212

Polymorphism screen data for oxalic acid •tetramethylpyrazine, 8 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

600

500

400

water 300 DMSO Relative Intensity Relative methanol 200 ethyl acetate

chloroform 100 toluene

cyclohexane 0

0 5 10 15 20 25 30 35 40 2-theta/deg

XRPD pattern is a mixture of co-crystal 8 and trace amounts of starting material.

213 Appendix 9. Experimental Data for isophthalic acid •1,2-bis(4-pyridyl)ethane, 9

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of isophthalic acid •1,2-bis(4-pyridyl)ethane, 9

100 ts504c isophthalic acid_bipethane in DMSO 98 96 94 92 90 88 86 1499.62 84 82 80

78 1417.58 %T 1696.85 76 1217.39 1609.42 1145.21 1277.77 74 1251.00 689.92 72 70 68 66 1018.25 1027.25 64 62 824.74 60 738.51

56 3000 2000 1000 Wavenumbers (cm-1)

214 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

2500

2000

1500

1000 Relative Inensity

500 simulated isophthalic acid _bipethane

isophthalic acid bipethane 0 0 5 10 15 20 25 30 35 40 2-theta/deg

215 600

400

simulated isophthalic _bipethane xtal Relative Intensity melt 200

solvent grind

grind 0 0 5 10 15 20 25 30 35 40 2-theta/deg

Polymorphism screen data for isophthalic acid •1,2-bis(4-pyridyl)ethane, 9. X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water.

600

500

400

300

200 Relative Intensity

100

0 5 10 15 20 25 30 35 40 2-theta/deg

Incomplete conversion as evidenced by XRPD, resulting in a mixture of co-crystal and trace amounts of starting materials. Only one form obtained.

216 Appendix 10. Experimental Data for (trimesic acid)2 • trans-(1,2-bis(4- pyridyl)ethylene)3, 11

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of (trimesic acid)2 •trans-(1,2-bis(4-pyridyl)ethylene)3, 11

ts503e bipethylene trimesic acid 3:2 102 100 98 96 94 92 90 3425.18

88 1418.71 1702.92 86 841.12

84 1170.01 1604.07

%T 82 301 80 78 688.81 823.13 76 746.24

74 953.19 72 70 68 66

64 1017.51 62

3000 2000 1000 Wavenumbers (cm-1)

217

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/eg

2500

2000

1500

1000 Relative Intensity Relative

simulated trimesic acid 500 _trans-1,2-bis(4-pyridyl)ethylene trimesic acid

0 trans-1,2-bis(4-pyridyl) ethylene

0 5 10 15 20 25 30 35 40 2-theta/deg

218 Polymorphism screen data for (trimesic acid)2 •trans-(1,2-bis(4-pyridyl)ethylene)3, 11 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

600

500

400

300 simulated trimesic acid _trans 1,2-(4-pyridyl) Relative Intensity Relative 200 ethylene xtal

trimesic acid 100

solvent grind 0

0 5 10 15 20 25 30 35 40 2-theta/deg

400

300

DMSO

200 methanol

ethyl acetate Relative Intensity

100 chloroform

toluene

cyclohexane 0

0 5 10 15 20 25 30 35 40 2-theta/deg

Solvent drop grinding for 4 minute results in a mixture of trimesic acid •1,2-bis(4-pyridyl)ethylene, 11 and trimesic acid in all cases except that of DMSO solvent grind in which complete conversion is achieved.

219 Appendix 11. Experimental Data for trimesic acid•1,2-bis(4-pyridyl)ethane, 12

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of trimesic acid•1,2-bis(4-pyridyl)ethane, 12

ts503c trimesic acid:1,2bis(4-pyridyl)ethane (2:3) 100

75 3410.66

70 1418.95 1701.63 65 1090.49 1221.89 1170.37 899.03 60 1609.91 %T 55 568 97

50 664.88 594.62 45

40 951.86 688.84 823.45 35 746.79 30

20 1018.50 15 3000 2000 1000 Wavenumbers (cm-1)

220

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

Form I

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

Form 2

221

2000

1500

1000 Simulated FormII

Relative Intensity Simulated Form I 500 TMA

bipethane 0

0 5 10 15 20 25 30 35 40 2-theta/deg

200

100 Relative Intensity

acetone 0 TMA bipethane

0 5 10 15 20 25 30 35 40 2-theta/deg

222 Polymorphism screen data for (trimesic acid)2 •(1,2-bis(4-pyridyl)ethane)3, 12 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

550

500 isopropanol 450 chloroform 400 dichloromethane cyclohexane 350 heptane 300 DMA amorphous 250 toluene DMSO ethyl acetate 200 THF

Relative Intensity acetonitrile 150 isopropyl aetate 100 ethanol methanol 50 acetone amorphous 1,2-bis(4-pyridyl)ethane 0 TMA Form I -50 Form II

0 5 10 15 20 25 30 35 40 2-theta/deg

Two different XRPD patterns are observed in the above solvent drop grind screen of 2:3 molar ratio of TMA and 1,2-bis(4-pyridyl)ethane and are grouped accordingly. Group A: Solvent drop grinds involving isopropanol, chloroform, dichloromethane, cyclohexane, heptane, ethyl acetate, tetrahydrofuran, acetonitrile, isopropyl acetate, methanol, heptane, DMA and DMSO. Group B: Solvent drop grinds involving toluene, acetone and ethanol. The solvent drop grinds were compared to the starting materials as well as co-crystal 12a (form I) and 12b (form II). Based upon this comparison the solvent drop grinds of group A were found to be a mixture of starting materials whereas group B appears to be a new form.

223 320

280

240

200 cyclohexane

160 Form II

Relative Intensity 120 Form I 80 1,2-bis(4-pyridyl)ethane 40

0 TMA

0 5 10 15 20 25 30 35 40 2-theta/deg

280

240

200 toluene

160 Form II

120 Form I Relative Intensity 80 1,2-bis(4-pyridyl)ethane 40

TMA 0

0 5 10 15 20 25 30 35 40 2-theta/deg

224 Appendix 12. Experimental Data for (1-naphthol)2 •1,2-bis(4-pyridyl)ethane, 13 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of (1- naphthol)2 •1,2-bis(4-pyridyl)ethane, 13.

80 1603.68 %T

75 1008.37 1283.50 1573.96 825.50

65 1389.64

60 793.63

3000 2000 1000 770.23 Wavenumbers (cm-1)

225

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

3500

3000

2500

2000 melt

solvent grind 1500 Relative Intensity 1000 grind calc. from single crystal 500 1,2-bis(4-pyridyl)ethane 0 1-naphthol

0 5 10 15 20 25 30 35 40 2-theta/deg

226 Appendix 13. Experimental Data for (1-naphthol)2 •trans-1,2-bis(4-pyridyl)ethylene, 14. Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of (1- naphthol)2 •trans-1,2-bis(4-pyridyl)ethylene, 14.

82 %T 80 1573.92

78 829.03 1007.50

76 1598.40

74 1390.28

70 793.31 68

66 64

3000 2000 1000 770.37 Wavenumbers (cm-1)

227

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

2500

2000 melt

1500 solvent drop grind

grind 1000 Relative Intensity calc from xtals 500 trans-1,2(4-pyridyl) ethylene 0 1-naphthol

0 5 10 15 20 25 30 35 40 2-theta/deg

228 Appendix 14. Experimental Data for 4,4’-biphenol •1,2-bis(4-pyridyl)ethane, 15

DSC and X-ray powder diffraction pattern of 4,4’-biphenol •1,2-bis(4-pyridyl)ethane, 15

10000

8000

6000 iIntensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

229

2500

2000

1500

1000 Relative Intensity Relative

simulated 4,4'-biphenol _1,2-bis(4-pyridyl)ethane 500 4,4'-biphenol

1,2-bis(4-pyridyl)ethane 0

0 5 10 15 20 25 30 35 40 2-theta/deg

3000

2500

2000

melt 1500

solvent grind

Relative Intensity 1000 grind

500 calculated fr. xtal 1,2-bis(4-pyridyl)ethane 0 4,4-biphenol

0 5 10 15 20 25 30 35 40 45 2-theta/deg

230 Appendix 15. Experimental Data for 4,4’-biphenol • trans-1,2-bis(4- pyridyl)ethylene, 16. Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 4,4’- biphenol • trans-1,2-bis(4-pyridyl)ethylene, 16.

102

100

%T 86

80 1166.65 740.06 1239.38 78 980.80

76 1005.96 1600.46 1497.33 74

70 1267.04 815.07 3000 2000 1000 Wavenumbers (cm-1)

231 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

3500

3000

2500

2000

solvent drop grind 1500

grind Relative Intensity 1000 calc. from xtals 500 grind trans-1,2(4-pyridyl) 0 ethylene 4,4-biphenol 0 5 10 15 20 25 30 35 40 2-theta/deg

232 Appendix 16. Experimental Data for hydroquinone • trans-1,2-bis(4- pyridyl)ethylene, 17 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of hydroquinone • trans-1,2-bis(4-pyridyl)ethylene, 17.

102

100

92 %T 1253.47

90 2923.35 976.74 1473.83 736.63 1601.62 88 757.03 806.07 1006.44 86 829.74 84

4000 3000 2000 1000 Wavenumbers (cm-1)

233

10000

8000

6000

Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

700

600

500

400

300 trans1,2(4-pyrdyl))ethylene

200 hydroquinone Relative Intensity calc. from xtal

100 melt

0 grind

-100 solvent grind

0 5 10 15 20 25 30 35 40 2-theta/deg

234 Appendix 17. Experimental Data for hydroquinone• tetramethylpyrazine, 18 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of hydroquinone• tetramethylpyrazine, 18.

102

100

92 %T 1519.07 90 1443.88 1235.42

88 820.62

86 1470.35 761.61 1420.33 84

82 1253.28 1214.43 4000 3000 2000 1000 Wavenumbers (cm-1)

235

10000

8000

6000 Intensity

4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

2000

1800

1600

1400

1200

1000

800 TMP

600

Relative Intensity hydroquinone 400 calc from xtal 200 melt

0 solvent grind

-200 grind

0 5 10 15 20 25 30 35 40 2-theta/deg

236 Appendix 18. Experimental Data for (resorcinol)2•(TMP)3, 19 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of (resorcinol)2•(TMP)3, 19.

101.5

101.0

100.5

100.0

99.5

99.0

98.5

98.0 %Transmittance 97.5

97.0 1220.96 1602.63 802. 15

96.5 969. 78

96.0 837. 01 1152.66 1183.72

95.5 1415.16

95.0 4000 3000 2000 1000 Wavenumbers (cm-1)

237

10000

8000

6000 Intensity 4000

2000

5 10152025303540 2-theta/deg

600

500

400

300 TMP Relative Intensity 200 resorcinol xtals from soln

100 solvent grind

melt 0 grind

0 5 10 15 20 25 30 35 40 2-theta/deg

238 Appendix 19. Experimental Data for 2,7-dihydroxynaphthalene● (TMP)2, 20 Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 2,7- dihydroxynaphthalene● (TMP)2, 20

106

104

102

100

%Transmittance 92

82 4000 3000 2000 1000 Wa ven umb er s ( cm- 1)

239 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1400

1200

1000

800 solvent grind 600 grind Relative Intensity 400

calc from xtal 200 TMP 0 2,7-DHN

0 5 10 15 20 25 30 35 40 2-theta/deg

240 Appendix 20. Experimental Data for (3-hydroxybenzoic acid)2 •pyrazine, 21

Infrared Spectrum and X-ray powder diffraction pattern of (3-hydroxybenzoic acid)2 •1,2- bis(4-pyridyl)ethane, 21.

100 98 96 94 92 90 88 86 84 82

%T 80 78 76 74 72 70 68 66 64 62

3000 2000 1000 Wavenumbers (cm-1)

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

241

1600

1400

1200

1000

800 melt 600

Relative Intensity alc. 3HB pyrazine 2 400 pyrazine 200 3HB Form II

0 3-HB Form I

0 5 10 15 20 25 30 35 40 45 2-theta/deg

New Phase obtained upon melt that does not correspond to calc. co-crystal XRPD pattern, has peaks that are shifted relative to starting materials and co-crystal.

1600

1400

1200

1000

800

600 grind

Relative Intensity calc. 3HB pyrazine 2 400 pyrazine 200 Form II

0 Form I

0 5 10 15 20 25 30 35 40 45 2-theta/deg

Dry grinding for 6 minutes yields phase that does not correspond to co-crystal, possibly a mixture of Form I and Form II 3-hydroxybenzoic acid

242 1600

1400

1200

1000

800 solvent-drop grind 600

Relative Intensity calc 3HB pyrazine 400 2 pyrazine 200 Form II 3HB

0 Form I 3HB

0 5 10 15 20 25 30 35 40 45 2-theta/deg

New Phase obtained that does not correspond to calc. co-crystal XRPD pattern, has peaks that are shifted relative to starting materials and co-crystal.

Polymorphism screen data for 3-hydroxybenzoic acid)2 •pyrazine 21 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

350

calc 3HB pyrazine xtal 300 2

methanol 250

toluene 200

150 water Relative Intensity

100 ethyl acetate

DMSO 50

0 cyclohexane 0 5 10 15 20 25 30 35 40 2-theta/deg

(3-hydroxybenzoic acid)2• pyrazine co-crystal reproduced from MeOH grind. Solvent drop grinding involving DMSO, ethyl acetate, water and cyclohexane produced a new phase that does not correspond to calc. co-crystal XRPD pattern and has peaks that are shifted relative to starting materials and co-crystal. Toluene grind appears to give a mixture of 3-hydroxybenzoic acid Form I and Form II exhibiting a similar pattern as seen in the dry grind.

243 Appendix 21. Experimental Data for 4-hydroxybenzoic acid •1,2-bis(4- pyridinium)ethane • 4- hydroxybenzoate, 22

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 4- hydroxybenzoic acid •1,2-bis(4-pyridinium)ethane • 4- hydroxybenzoate, 22.

100

84 %T 82

66 4000 3000 2000 1000 Wavenumbers (cm-1)

244 10000

8000

6000

4000 Relative Intensity Relative

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1600

1400

1200

1000 melt

800 solvent drop grind

600 dry grind Relative Intensity

400 calc. XRPD xtal

200 1,2-bis(4-pyridyl)ethane

0 4HB

0 5 10 15 20 25 30 35 40 45 2-theta/deg

Co-crystal obtained from melt, grind and solvent drop grind resulted in mixture of starting materials

245 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water

2500

2000 toluene

1500 methanol ethyl acetate

1000

Relative Intensity dmso cyclohexane 500 calc. XRPD xtal 1,2-bis(4-pyridyl)ethane 0 4HB

0 5 10 15 20 25 30 35 40 2-theta/deg

A search for crystal forms using solvent drop grinding yield new crystalline phase that contain peaks that do not correspond to isolated single crystal or starting materials

246 Appendix 22. Experimental Data for (4-hydroxybenzoic acid)2 •tetramethylpyrazine, 23

Infrared Spectrum and X-ray powder diffraction pattern of (4-hydroxybenzoic acid)2 •tetramethylpyrazine, 23

ts434d TMpyrazine/4-hydroxybenzoic acid 108 106 104 102 100 98 96 94 92 90 %T 88 86 84 82 80 78 76 74 72 70

3000 2000 1000 Wavenumbers (cm-1)

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

247 1800

1500

1200

melt 900 solvent drop grind

Relative Intensity 600 grind calc from xtal 300 TMP

0 4HB

0 5 10 15 20 25 30 35 40 2-theta/deg

Melt, solvent drop grind and dry grind yield the co-crystal as well as starting materials.

X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene ethyl acetate, methanol, water and DMSO

toluene

water

1000 methanol

ethyl acetate

DMSO Relative Intensity cyclohexane

calc from xtal

TMP

0 4HB

5 10152025303540 2-theta/deg

Water, methanol and ethyl acetate grind contain additional peaks that are not present in either co-crystal or starting materials. Complete conversion to co-crystal from DMSO grind whereas peaks corresponding to 4- hydroxybenzoic acid are present in cyclohexane and toluene grinds.

248 Appendix 23. Experimental Data for 4-hydroxybenzoic acid • 4-phenylpyridine, 24

Infrared Spectrum and X-ray powder diffraction pattern of 4-hydroxybenzoic acid • 4- phenylpyridine, 24.

ts458d 4-phenylpyridine_4-hydroxybenzoic acid 108

106

104

102

100

%T 90

74 72 3000 2000 1000 Wavenumbers (cm-1)

10000

8000

6000

Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

249

1400

1200

1000

800 melt

600 solvent drop grind

Relative Intensity grind 400

calc from xtal 200 4phenylpyridine 4HB 0 0 5 10 15 20 25 30 35 40 45 2-theta/deg

Peak shifts as compared to co-crystal and starting material evident in melt and solvent drop grind. Dry grind appears to be a mixture of starting materials

X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water

2000

cyclohexane 1500

tol

1000 methanol

Relative Intensity ethyl acetate

500 dmso calc. from xtal 4-phenylpyridine 0 4HB 0 5 10 15 20 25 30 35 40 45 2-theta/deg

MeOH and EtoAc grinds results in mixture of starting materials, DMSO grinds have peaks corresponding to co-crystals however peaks at higher 2θ values are shifted relative to the co-crystal

250 Appendix 24. Experimental Data for (4-hydroxybenzoic acid)2 •pyrazine, 25

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of (4- hydroxybenzoic acid)2 •pyrazine, 25

102 ts441b pyrazine/4-hydroxybenzoic acid 1:2 in acetonitrile

100

88 %T 86

3000 2000 1000 Wavenumbers (cm-1)

251

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1800

1500

1200

900 melt

solvent-drop grind 600 Relative Intensity

grind 300 calc. fr. xtal pyrazine 0 4HB 0 5 10 15 20 25 30 35 40 2-theta/deg

252 1500

water 1200 toluene

900 methanol

ethyl acetate 600

Relative Intensity dmso

300 cyclohexane calc fr. xtal pyrazine 0 4HB

0 5 10 15 20 25 30 35 40 2-theta/deg

New crystalline phase obtained that contain peaks that are not present or are shifted relative to co-crystal and starting materials.

253 Appendix 25. Experimental Data for 4-hydroxybenzoic acid)2 •tetramethylpyrazine acetonitrile solvate, 26

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of (4- hydroxybenzoic acid)2 •tetramethylpyrazine acetonitrile solvate, 26

101 ts 78 8c 100

91 %Transmitt ance 90

84 83 3000 2000 1000 Wavenumbers (cm-1)

254 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1200 1100 1000 900 800 700 acetonitile 600 500 calc. 4HB TMP acetonitrile 400 2 Relative Intensity 300 sovate 200 TMP 100 0 4HB -100 0 5 10 15 20 25 30 35 40 2-theta/deg

Acetonitrile grind does not yield the (4-hydroxybenzoic acid)2 tmp acetonitrile solvate

255 Appendix 26. Experimental Data for 3-hydroxybenzoic acid •(4-phenylpyridine)2, 27

Experimental Data for Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3-hydroxybenzoic acid •(4-phenylpyridine)2, 27

ts480b 4-phenylpyridine_3-hydroxybenzoic acid 101

100

96 %T

90 3000 2000 1000 Wavenumbers (cm-1)

256 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

2400

2000

1600

melt 1200 solvent grind

grind Relative Intensity 800 calc. fr. 3HB_4pp 2

400 4-phenylpyridine Form II 3HB

0 Form I 3HB

0 5 10 15 20 25 30 35 40 2-theta/deg

The co-crystal is reproduced from the melt. A mixture of the co-crystal and starting material was obtained from dry grind and acetone solvent drop grind.

257 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water

2400

2100 water

1800 toluene

1500 methanol

1200 ethyl acetate dmso 900

Relative Intensity cyclohexane

600 calc. fr. xtal 4-phenylpyridine 300 Form II 3HB

0 Form I 3HB

0 5 10 15 20 25 30 35 40 2-theta/deg

Solvent drop grinding for 4minutes yield a mixture of co-crystal and starting materials, peak shift ca. 27

258 Appendix 27. Experimental Data for 3-hydroxybenzoic acid •1,2-bis(4- pyridyl)ethane, 28

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3- hydroxybenzoic acid •1,2-bis(4-pyridyl)ethane, 28

100 ts480e bipethane_3-hydroxybenzoic acid in MeOH/EtOH

%T 93

86 3000 2000 1000 Wavenumbers (cm-1)

259 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

2400

2000

1600

1200 melt

Relative Intensity 800 calc fr. xtal

400 1,2bis(4-pyridyl)ethane Form II 3HB

0 Form I 3HB

0 5 10 15 20 25 30 35 40 2-theta/deg

Co-crystal produced from the melt.

260 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO and water

1600

1400

1200

1000

800 grind water 600 Relative Intensity DMSO 400 methanol ethyl acetate 200 chloroform toluene 0 cyclohexane

0 5 10 15 20 25 30 35 40 2-theta/deg

Dry grind and solvent drop grinds give a mixture of co-crystal and starting materials

261 Appendix 28. Experimental Data for 3-hydroxybenzoic acid •4,4’-bipyridine, 29

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3- hydroxybenzoic acid •4,4’-bipyridine, 29.

106 ts480d bipy/3-hydroxybenzoic acid in EtOH/MeOH

104

102

100

%T 92

3000 2000 1000 Wavenumbers (cm-1)

262

10000

8000

6000

Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1800

1600

1400

1200

1000 melt

800 grind

Relative Intensity 600 calc. fr. xtal

400 4,4'-bipyridine

200 3HB Form II 3HB Form I 0

0 5 10 15 20 25 30 35 40 2-theta/deg

Dry grind for 4 minutes gives a mixture of starting materials as well as a peak ca. 27 2θ that is present in co-crystal. Co-crystal is produced from the melt.

263 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO and water

900

800

700

600

500

400 calc. from xtal water dmso Relative Intensity 300 chloroform 200 methanol toluene 100 ethyl acetate cyclohexane 0 grind

5 101520253035 2-theta/deg

Co-crystal is reproduced from solvent drop grindings involving methanol, cyclohexane, water and dmso, all other solvent and dry grind produce the co-crystal as well as starting materials.

264 Appendix 29. Experimental Data for 3-hydroxybenzoic acid •quinoxaline, 30

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3- hydroxybenzoic acid •quinoxaline, 30.

ts447 quinoxaline_3-hydroxybenzoic acid 100

95 %T 94

3000 2000 1000 Wavenumbers (cm-1)

265 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1400

1200

1000

800

dry grind 600 Relative Intensity 400 calc. from xtal

quinoxaline 200 Form II 3HB

0 Form 3HB

0 5 10 15 20 25 30 35 40 2-theta/deg

Dry grind gives mixture of co-crystal and starting materials.

266 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water

2400

2000 water toluene 1600 methanol ethyl acetate 1200 cyclohexane 800 Relative Intensity dmso

400 calc fr. xtal quinoxaline

0 FormII 3HB Form I 3HB

0 5 10 15 20 25 30 35 40 2-theta/deg

Solvent drop grind results in mixture of co-crystal and starting materials

267 Appendix 30. Experimental Data for (3-hydroxybenzoic acid)2 • (tetramethylpyrazine)3, 31

DSC thermogram and X-ray powder diffraction pattern of (3-hydroxybenzoic acid)2 • (tetramethylpyrazine)3, 31.

10000

8000

6000

Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

268 1800

1600

1400

1200

1000 melt

800 acn grind

Relative Intensity 600 grind 400 calc. fr. xtal 200 TMP 3HB Form II 0 3HB Form I 0 5 10 15 20 25 30 35 40 2-theta/deg

Melt produces co-crystal 31, grind gives mixture of starting materials

X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water

2400

2000 ethyl acetate

1600 water toluene

1200 methanol dmso

Relative Intensity 800 clohexane cal fr. xtal 400 TMP Form II 3HB

0 Form I 3HB

0 5 10 15 20 25 30 35 40 2-theta/deg

Ethyl acetate grind gives new crystalline phase, mixture of starting material and co-crystals obtained from other solvent drop grinds.

269 Appendix 31. Experimental Data for 6-hydroxy-2-naphthoic acid • trans-1,2-bis(4- pyridyl)ethylene, 32

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 6-hydroxy- 2-naphthoic acid • trans-1,2-bis(4-pyridyl)ethylene, 32

104 ts460d bipethylene_6-hydroxy-2-naphthoic acid in EtOH

102

100

%T 92

80 3000 2000 1000 Wavenumbers (cm-1)

270

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

271 Appendix 32. Experimental Data for 4-hydroxybenzoic acid • trans-1,2-bis(4- pyridyl)ethylene, 33

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 4- hydroxybenzoic acid • trans-1,2-bis(4-pyridyl)ethylene, 33.

108 ts461a bipethylene/4-hydroxybenzoic acid 1:1 in MeOH

106

104

102

100

92 %T 90

74 3000 2000 1000 Wavenumbers (cm-1)

272 10000

8000

6000

Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

3000

2500

2000

1500

1000 dry grind Relative Intensty

calc. fr. xtal 500

trans-1,2-bis(4-pyridyl)ethylene 0 4-hydroxybenzoic acid

0 5 10 15 20 25 30 35 40 2-theta/deg

Grind results in a mixture of starting materials

273 Appendix 33. Experimental Data for 3-hydroxybenzoic acid • trans-1,2-bis(4- pyridyl)ethylene, 34

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3- hydroxybenzoic acid • trans-1,2-bis(4-pyridyl)ethylene, 34.

ts 460b bipethylene/3-hydroxybenzoic acid 1:1 102

100

94 %T 92

3000 2000 1000 Wavenumbers (cm-1)

274 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1400

1200

1000

800

grind 600

Relative Intensity calc. from xtal 400

trans_1,2-bis(4-pyridyl)ethylene 200 3HB Form II 0 3HB Form I

0 5 10 15 20 25 30 35 40 2-theta/deg

Grind results in a mixture of starting materials

275 Appendix 34. Experimental Data for 3-hydroxypyridinium benzoate, 35

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3- hydroxypyridinium benzoate, 35.

104

102

100

92 1069.68 1508.09

90 837.10 1579.71 982.50 1168.70 88 %T 86 1353.75 84 1390.25 82

80 1293.11 802.59 78 675. 93 76

72 722.75 70 4000 3000 2000 1000 cm-1

276 10000

8000

6000

Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1800

1500

1200

900 Relative IntensityRelative 600

300 3-hydroxypyridinium benzoate benzoic acid

0 3-hydroxypyridine

0 5 10 15 20 25 30 35 40 2-theta/deg

277 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water

700

600

500 water

400 DMSO

300 toluene Relative Intensity

200 ethyl acetate

100 methanol

0 cyclohexane

0 5 10 15 20 25 30 35 40 2-theta/deg

Solvent drop grinding yields organic salt of 3-hydroxypyridinium benzoate

278 Appendix 35. Experimental Data for 3-hydroxypyridinium isophthalate, 36

Infrared Spectrum, DSC thermogram and X-ray powder diffraction pattern of 3- hydroxypyridinium isophthalate, 36.

105

100

80 %T

4000 3000 2000 1000 Wavenumbers (cm-1)

279

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 2-theta/deg

1000

800

600

400 Relative Intensity 3-hydroxypyridinium 200 isophthalate

isophthalic acid

0 3-hydroxypyridine

0 5 10 15 20 25 30 35 40 2-theta/deg

250

200

150

100 Relative Intensity grind 50

0 calc. fr. xtal

0 5 10 15 20 25 30 35 40 2-theta/deg

280 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO and water

400

350

300

250 water

200 DMSO

150 methanol

Relative Intensity toluene 100 ethyl acetate 50

0 cyclohexane

0 5 10 15 20 25 30 35 40 2-theta/deg

281 Appendix 36. X-ray powder diffraction patterns of grinding and solvent drop grinding of isonicotinic acid •1-naphthol, nicotinic acid •1-naphthol, (nicotinic acid)2 •4,4’-biphenol, (isonicotinic acid)2 •4,4’-biphenol, (isonicotinic acid)3 •phloroglucinol, (nicotinic acid)3 •phloroglucinol, (isonicotinic acid)2 •resorcinol, (nicotinic acid)2 •resorcinol.

2500

2000 no solvent MeoH solv grind 1500 water solv grind dmso solv grind 1000 cyclohexane solv grind toluene solv grind Relative Intensity Relative chloroform solv grind 500 EtOAc solv grind isonicotinic acid

0 1-naphthol

5 1015202530354045 2-theta/deg

2500

2000 no solvent

meoh grind 1500 water grind dmso grind 1000 cyclohexane grind toluene grind Relative Intensity

chloroform grind 500 EtOAc grind nicotinic acid 1-naphthol 0

5 1015202530354045 2-theta/deg

282

2500

2000 no solvent methanol grind 1500 water grind

dmso grind

1000 cyclohexane grind

Relative Intensity chloroform grind toluene grind 500 EtOAc grind

nicotinic acid

0 4,4'-biphenol

5 1015202530354045 2-theta/deg

2600 2400 2200 2000 no solvent

1800 MeOH grind 1600 water grind 1400 DMSO grind

1200 cyclohexane grind

1000 toluene grind Relative Intensity 800 chloroform grind 600 EtoAc grind

400 nicotinic acid 200 phloroglucinol 0 0 5 10 15 20 25 30 35 40 45 2-theta/deg

283 2500

2000 no solvent MeOH grind

water grind 1500 DMSO grind cyclohexane grind

1000 toluene grind chloroform grind Relative Intensity

EtOAc grind 500 isonicotinic acid

phloroglucinol dihydrate

0 phloroglucinol

5 1015202530354045 2-theta/deg

2200 2000 1800 MeOH grind 1600 water grind

1400 dmso grind

1200 cyclohexane grind 1000 toluene grind 800 chloroform grind

Relative Intensity 600 EtOac grind

400 no solvent 200 resorcinol bulk 0 isonicotinic bulk sim_isonicotinic -200 sim_resorcinol

5 1015202530354045 2-theta/deg

284 2000

no solvent

MeOH grind 1500 water grind

DMSO grind

1000 cyclohexane grind

toluene grind

choroform grind Relative Intensity 500 EtOAc grind

resorcinol

0 nicotinic acid sim_resorcinol

0 5 10 15 20 25 30 35 40 45 2-theta/deg

285 Appendix 37. DSC thermograms for the attempted co-crystallizations of 5- hydroxyisoquinoline•benzoic acid, 5-hydroxyisoquinoline • sorbic acid, (5- hydroxyisoquinoline)2 • isophthalic acid, (5-hydroxyisoquinoline)2 • glutaric acid, (5-hydroxyisoquinoline)3 • trimesic acid, 3-hydroxypyridine • sorbic acid, (3- hydroxypyridine)2 • glutaric acid, (3-hydroxypyridine)3 • trimesic acid.

DSC thermogram for the solvent drop grinding of 1:1 mole ratio of 5- hydroxyisoquinoline and benzoic acid

DSC thermogram comparing the solvent drop grind of 5-hydroxyisoquinoline and benzoic acid versus starting materials

286 DSC thermogram for the solvent drop grinding of 1:1 mole ratio of 5- hydroxyisoquinoline and sorbic acid

DSC thermogram comparing solvent drop grind 5-hydroxyisoquinoline and sorbic acid versus starting materials

287 DSC thermogram for the solvent drop grinding of 2:1 mole ratio of 5- hydroxyisoquinoline and glutaric acid

DSC thermogram comparing solvent drop grind 5-hydroxyisoquinoline and glutaric acid versus starting materials

288 DSC thermogram for the solvent drop grinding of 2:1 mole ratio of 5- hydroxyisoquinoline and isophthalic acid

DSC thermogram comparing solvent drop grind 5-hydroxyisoquinoline and isophthalic acid versus starting materials

289

DSC thermogram for the solvent drop grinding of 3:1 mole ratio of 5- hydroxyisoquinoline and trimesic acid

DSC thermogram comparing solvent drop grind 5-hydroxyisoquinoline and trimesic acid versus starting materials

290 DSC thermogram showing comparison of solvent drop grind of 3-hydroxpyridine and benzoic acid versus single crystals of 3-hydroxypyridinium benzoate

291

DSC thermogram for the solvent drop grinding of 2:1 mole ratio of 3-hydroxypyridine and isophthalic acid

DSC thermogram comparing solvent drop grind 3-hydroxypyridine and isophthalic acid versus starting materials

292 DSC thermogram for the solvent drop grinding of 1:1 mole ratio of 3-hydroxypyridine and sorbic acid

DSC thermograms comparing solvent drop grind 3-hydroxypyridine and sorbic acid versus starting materials

293 DSC thermogram for the solvent drop grinding of 2:1 mole ratio of 3-hydroxypyridine and glutaric acid

DSC thermograms comparing solvent drop grind 3-hydroxypyridine and glutaric acid versus starting materials

294 X-ray powder Diffraction of attempted co-crystallization of 3-hydroxypyridine and sorbic acid

700

600

500

400 Intensity 300

200

100

0 5 10 15 20 25 30 35 40 2-theta/deg

Histogram showing contact distance for alcohol-carbonyl (acid) interactions

30 y 25

20 Frequenc 15

0 2.5 2.6 2.7 2.8 2.9 3 3.1 3.2 3.3 3.4 3.5 alcohol-carbonyl(acid) O-H...O Hydrogen bond

There are 1495 entries that contain both a carboxylic acid and an alcohol. Of this number 566/1495 (37%) exhibit the alcohol-carbonyl heterosynthon. The interaction was found to occur within the range 2.6-3.0Å, Mean: 2.80(8) Å

Search Filters: CSD 5.28, Jan 2007 update: Organics only, 3D coordinates determined, R>7.5%.

295 Tabulated pKa values of existing CSD structures containing 3-hydroxypyridine

REFCODE Compound Pka (acid) Pka (base) ΔPka(base- acid)

IDUNEA 3-hydroxypyridinium_ 5- 2.06 8.51 6.45 nitrofuran-2-carboxylate 4.86

IDUNIE 3-hydroxypyridinium_ 4- 3.42 8.51 5.09 nitrobenzoate 4.86

IDUNOK 3-hydroxypyridinium_ 2,4- 1.43 8.51 7.08 dinitrobenzoate 4.86

IDUNUQ 3-hydroxypyridinium_3,5- 2.77 8.51 5.74 dinitrobenzoate 4.86

JOJJUN 3-hydroxypyridinium_2,4,6- 0.42 8.51 8.09 trinitrobenzoate 4.86

KOKBOC 3-hydroxypyridinium_(2,4- 2.98 8.51 5.53 dichlorophenoxy acetate 4.86

LEJROH 3-hydroxypyridinium_ pyrazine- 2.24 8.51 6.27 2,6-dicarboxylate -4.01 4.86

OCAKAF 3-hydroxypyridinium_3- 2.83 8.51 5.68 (carboxymethoxy)phenoxy acetate 4.86

PAHZAA 3-hydroxypyridinium_2- 1.98 8.51 6.53 hydroxypropanedioate 4.86

RACBED 3-hydroxypyridinium_2,5- 3.01 8.51 5.50 dihydroxybenzoate 4.86

VITXUR 3-hydroxypyridinium tartrate 3.07 8.51 5.44

4.86

YETLUE 3-hydroxypyridinium_L-malate 3.61 8.51 4.90

4.86

296 Tabulated pKa values for components used in attempted co-crystallization involving molecules containingOH/Narom with COOH melecules

pKa (base) pKa(acid) ΔpKa

3-hydroxypyridine and sorbic 8.51 4.59 3.92 acid 4.86

3-hydroxypyridine and glutaric 8.51 4.33 4.18 acid 4.86

3-hydroxypyridine and trimesic 8.51 2.98 5.53 acid 4.86

5-hydroxyisoquinoline and 8.31 4.2 4.11 benzoic acid 5.31

5-hydroxyisoquinoline and 8.31 4.59 3.72 sorbic acid 5.31

5-hydroxyisoquinoline and 8.31 4.33 3.98 glutaric acid 5.31

5-hydroxyisoquinoline and 8.31 3.53 4.78 isophthalic acid 5.31

5-hydroxyisoquinoline and 8.31 2.98 5.53 trimesic acid 5.31

297 Appendix 39. Experimental Data for (stavudine)3 •melamine, 37

DSC thermogram, FT-IR spectrum and X-ray powder diffraction patterns of bulk sample and calculated from the single crystal structure for (stavudine)3 •melamine, 37

100

%T 93

92 1044.12 649.39 690.05

91 763.90 1268.32

90 1541.58 1091.10 1113.48 614.42 1688.16

89 1446.35

88 799.18 87 1654.93

4000 3000 2000 1000 Wavenumbers (cm-1)

298

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 45 2-theta/deg

299 Polymorphism screen data: X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, ethyl acetate, methanol, DMSO, and water.

140

120

water 100

toluene 80

methanol 60

Relative Intensity ethyl acetate 40

dmso 20

cyclohexane 0

0 5 10 15 20 25 30 35 40 2-theta/deg

Comparison of X-ray powder diffraction patterns of bulk sample obtained via slurry in water and calculated from the single crystal structure

simulated PXRD stavudine_melamine co-crystal 1400 slurry stavudine_melamine stavudine

1200

1000

800

600

400 Relative Intensity

200

0 5 10 15 20 25 30 35 40 45 2-theta/deg

300 Appendix 40. Experimental Data for stavudine •2,4,6-triaminopyrimidine hydrate, 38.

X-ray powder diffraction patterns calculated from the single crystal structure for stavudine •2,4,6-triaminopyrimidine hydrate, 38. 99

%Transmitt ance 88

81 80 4000 3000 2000 1000 Wavenumbers (cm-1)

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 45 2-theta/deg

301 Comparison of X-ray powder diffraction patterns of bulk sample obtained via slurry in water and calculated from the single crystal structure

Simulated PXRD stavudine_2,4,6-TAP hydrate Slurry Stavudine_2,4,6-TAP

700

600

500

400

300 Relative Intensity 200

100

5 10152025303540 2-theta/deg

302 Appendix 41. Experimental Data for stavudine•2-aminopyridine, 39 DSC termogram, FT-IR spectrum and X-ray powder diffraction patterns of stavudine•2- aminopyridine, 39.

100

%T 86 973.76

84 1220.71 1089.19 850.31 1106.59 758.85 82 801.22 738.49 1433.42

80 1628.96 816.94 78 1698.04 1666.28

76 1075.11

74 575.92

72 774.17 4000 3000 2000 1000 Wavenumbers (cm-1)

303

10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 45 2-theta/deg

1600

1400

1200

1000

800

600 Relative Intensity Relative simulated stavudine 400 _2-aminopyridine xtals

stavudine 200

2-aminopyridine 0

0 5 10 15 20 25 30 35 40 2-theta/deg

304 450

400

350

300 melt

250

200 solvent grind

150 Relative Intensity

100 grind

50 simulated stavudine 0 _2-aminopyridine

0 5 10 15 20 25 30 35 40 2-theta/deg

Polymorphism screen: X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water.

600

400

Relative Intensity Relative 200

0 5 10 15 20 25 30 35 40 2-theta/deg

305 Comparison of X-ray powder diffraction patterns of bulk sample obtained via slurry in water and calculated from the single crystal structure

Simulated PXRD ts369e 1200 Slurry stavudine_2-aminopyridine

1000

800

600

400

Intensity 200

0 5 10 15 20 25 30 35 40 45 2-theta

306 Appendix 42. Experimental Data for stavudine•4-hydroxybenzoic acid, 40 DSC termogram, FT-IR spectrum and X-ray powder diffraction patterns of stavudine•4- hydroxybenzoic acid, 40.

102

100

%T 86

80 1596.88 798.93 817.18

78 1280.99 616.84 1073.55 76 1241.29 74 850.71

4000 3000 2000 1689.08 1000 Wavenumbers (cm-1)

307 10000

8000

6000 Intensity 4000

2000

0 5 10 15 20 25 30 35 40 45 2-theta/deg

800

700

600

500

400

simulated XRPD stavudine 300 _4-hydroxybenzoic acid xtal Relative Intensity

200 stavudine

100 4-hydroxybenzoic acid 0

-100 0 5 10 15 20 25 30 35 40 2-theta/deg

308 700

600

500

400

300 melt

Relative Intensity Relative solvent grind 200

100 grind

simulated stavudine 0 _4-hydroxybenzoic acid xtal

0 5 10 15 20 25 30 35 40 2-theta/deg

Polymorphism screen data for stavudine•4-hydroxybenzoic acid, 40 X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO, and water.

1000

800

600

400 Relative Intensity

200

0 5 10 15 20 25 30 35 40 2-theta/deg

309 Comparison of X-ray powder diffraction patterns of bulk sample obtained via slurry in water and calculated from the single crystal structure

Simulated PXRD Stavudine_4-hydroxybenzoic acid co-crystal Slurry Stavudine_ 4-hydroxybenzoic acid

1000

800

600

400 Relative Intensity

200

5 10152025303540 2-Theta/deg

310 Appendix 43. Experimental Data for stavudine• salicylic acid 41 DSC termogram, FT-IR spectrum and X-ray powder diffraction patterns of bulk sample and calculated from the single crystal structure of stavudine• salicylic acid, 41

103

102 101

100

96 95

%T ransmittance 92

91 90

85 84 4000 3000 2000 1000 Wavenumbers (cm-1)

311

10000

8000

6000

Intensity 4000

2000

0 5 10 15 20 25 30 35 40 45 2-theta/deg

700

600

500

400

300 Relative Intensity simulated stavudine 200 _salicylic acid

stavudine 100

salicylic acid 0

0 5 10 15 20 25 30 35 40 2-theta/deg

312 500

450

400

350

300 melt

250

200 grind

150 Relative intensity Relative

100 solvent grind

0 simulated stavudine _salicylic acid -50 0 5 10 15 20 25 30 35 40 2-theta/deg

Polymorphism Screen for stavudine •salicylic acid, 41: X-ray powder diffraction patterns of powders obtained based upon solvent-drop grinding with: cyclohexane, toluene, chloroform, ethyl acetate, methanol, DMSO and water

800

600

400 Relative Intensity

200

0 5 10 15 20 25 30 35 40 45 2-theta/deg

313 Comparison of X-ray powder diffraction patterns of bulk sample obtained via slurry in water and calculated from the single crystal structure

Simulated PXRD Stavudine-salicylic acid co-crystal Slurry Stavudine_Salicylic acid 1200

1000

800

600

400 Relative Intensity

200

5 10152025303540 2-Theta/deg

314

About the Author

Tanise Shattock received her Bachelor’s degree in Chemistry from the University of West Indies, Kingston, Jamaica in 1998. In 2002, Tanise entered the Ph. D program at the University of South Florida and joined Dr. Michael J. Zaworotko’s research group.

While in the Ph.D. program she obtained a Research Assistantship from TransForm

Pharmaceuticals Inc. and was awarded the 2006-2007 Merck Research Laboratories

Graduate Fellowship in Chemistry, Pharmaceutical Science, Material Science, and

Engineering as well as the Florida Caribbean Scholarship 2003-2006. Tanise is a co- inventor on two patent applications and has co-authored several scientific publications.

She has presented her research at regional and national scientific meetings of the

American Chemical Society, American Crystallographic Association and International

Quality & Productivity Center.

315